RU2532481C2 - Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives, useful as rho-kinase inhibitors - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to bi- and polycyclic substituted isoquinoline and isoquinolinones of formula (I), or to its stereoisomeric and/or tautomeric forms and/or to its pharmaceutically acceptable salts, where Rrepresents OH; R, R, Rand Rrepresents H; Rrepresents halogen or (C-C) alkyl; Rrepresents one (C-C)alkylene, bound to a cycloalkyl ring, in which (C-C)alkylene forms the second bond with the other carbon atom of the cycloalkyl ring with the formation of a bicyclic ring system, where in the bicyclic ring system one carbon atom is substituted with a group, independently selected from O, S or SO; and if m and s equal 2 or m equals 3 and s equals 1, Rrepresents a group CH-CH-(CH), which via one group CHis bound to the cycloalkyl ring, and two other CHgroups are bound to different carbon atoms of the cycloalkyl ring, and if m equals 3 and s equals 3, Rrepresents two methylene groups, bound to different carbon atoms of the cycloalkyl ring, where the methylene groups or group CH-CH-(CH)are bound to the carbon atoms of the cycloalkyl ring and form an adamantane system of formula (XX), where L can be bound to any secondary or tertiary carbon atom, or Rtogether with Rand an N atom form (C) heterocycloalkyl, bound with the cycloalkyl residue in the form of a spirocyclic ring system, where the bicyclic ring system, or the adamantane system, or a ring system, containing (C) heterocycloalkyl, represent non-substituted or optionally substituted with substituent R; Rrepresents (C-C)alkyl, (C-C)alkenyl, (C)aryl or cyclopropyl Rand Rindependently on each other represent H or (C-C)alkylene-(C)aryl; n equals 0 or 1; m equals 2 or 3; s equals 1, 2 or 3; L represents O; its stereoisomeric and/or tautomeric forms and/or its pharmaceutically acceptable salts. The invention also relates to the application of a formula (I)compound.EFFECT: novel bi- and polycyclic isoquinoline and isoquinolinone derivatives, useful as inhibitors of Rho-kinase, are obtained.22 cl, 22 ex

Description

The present invention relates to bi- and polycyclic substituted derivatives of isoquinoline and isoquinolinone, their preparation, pharmaceutical preparations containing these derivatives, and their use in the treatment and / or prevention of diseases associated with the inhibition of Rho kinase and / or Rho-mediated phosphatase phosphorylation phosphoryase light chains of myosin.

The activation of small RhoA GTPases upon stimulation of the agonist leads to the conversion of RhoA from an inactive GDP-linked form to an active GDP-linked form, followed by binding to the Rho kinase and activation of the Rho kinase. Two isoforms are known, Rho kinase 1 and Rho kinase 2. Rho kinase 2 is expressed in vascular smooth muscle cells and endothelial cells. Activation of Rho kinase 2 by active GTP-linked RhoA leads to calcium sensitization of smooth muscle cells by phosphorylation-mediated inhibition of myosin light chain phosphatase activity and thereby increased regulation of myosin regulatory light chain activity (Uehata et al. Nature 1997, 389, 990-994) .

It is known that Rho kinase is involved in vasoconstriction, including the development of myogenic tone and hypercontractivity of smooth muscles (Gokina et al. J. Appl. Physiol. 2005, 98, 1940-1948), contraction of bronchial smooth muscles (Yoshii et al. Am. J. Resp. Cell Mol. Biol. 1999, 20, 1190-1200), asthma (Setoguchi et al. Br. J. Pharmacol. 2001, 132, 111-118; Nakahara et al. Eur. J. Pharmac. 2000, 389 103-106) and chronic obstructive pulmonary disease (COPD, Maruoka et al. Nippon Rinsho, 1999, 57, 1982-1987), hypertension, pulmonary hypertension (Fukumoto et al. Heart 2005, 91, 391-392, Mukai et al . Nature 1997, 389, 990-994) and eye hypertension and regulation of intraocular pressure (Honjo et al. Invest. Ophthalmol. Visual Sci. 2001, 42, 13 7-144), endothelial dysfunction (Steioff et al. Eur. J. Pharmacol. 2005, 512, 247-249), angina pectoris (Masumoto et al. Circulation 2002, 105, 1545-47, Shimokawa et al. J. Cardiovasc. Pharmacol. 2002, 40, 751-761), nephropathy, including nephropathy caused by hypertension, nephropathy not caused by hypertension, and diabetic nephropathy, renal failure, and peripheral arterial occlusive disease (PAOD) (Wakino et al. Drug News Perspect. 2005, 18, 639-643), myocardial infarction (Demiryurek et al. Eur. J. Pharmacol. 2005, 527, 129-140, Hattori et al. Circulation 2004, 109, 2234-2239), heart hypertrophy and heart failure ( Yamakawa et al. Hypertension 2000, 35, 313-318; Liao et al. Am. J. Physiol. Cell Physiol. 2006, 290, C661-668; Kishi et al. Circulation 2005, 111, 2741-2747), coronary artery disease heart, atherosclerosis, restenosis (Pacaud et al. Arch. Mal. Coeur 2005, 98, 249-254; Retzer et al. FEBS Lett. 2000, 466, 70-74; Negoro et al. Biochem. Biophys. Res. Commun. 1999, 262, 211-215), diabetes, diabetic complications, glucose utilization and metabolic syndrome (Sandu et al. Diabetes 2000, 49, 2178-2189; Maeda et al. Cell Metab. 2005, 2, 119-129), sexual dysfunction, e.g. impotence (Chitaley et al. Na ture Medicine 2001, 7, 119-122), retinopathy, inflammation, immune diseases, AIDS (AIDS), osteoporosis, endocrine dysfunctions, such as hyperaldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara et al. J. Neurosurg. 2000, 93, 94-101), cerebral ischemia (Uehara et al. Nature 1997, 389, 990-994; Satoh et al. Life Sci. 2001, 69, 1441-1453; Hitomi et al. Life Sci. 2000, 67, 1929-1939; Yamamoto et al. J. Cardiovasc. Pharmacol. 2000, 35, 203-211), cerebrovascular spasm (Sato et al. Circ. Res. 2000, 87, 195-200; Kim et al. Neurosurgery 2000, 46, 440-447), pain, for example, neuropathic pain (Tatsumi et al. Neuroscience 2005, 131, 491-498; Inoue et al. Nature medicine 2004, 10, 712-718), infectious diseases of the intestinal tract, caused by bacteria (WO 98/06433), the development and progression of cancer, neoplasia, where, as shown, inhibition of Rho kinase inhibits the growth and metastasis of tumor cells (Itoh et al. Nature Medicine 1999, 5, 221-225; Somlyo et al. Biochem. Biophys. Res. Commun. 2000, 269, 652-659), angiogenesis (Uchida et al. Biochem. Biophys. Res. Commun. 2000, 269, 633-640 ; Gingras et al. Biochem. J. 2000, 348, 273-280), proliferation and motility of vascular smooth muscle cells (Tammy et al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis 2001, 155, 321-327), endothelial cell proliferation, endothelial cell retraction and motility (Oikawa et al. Biochem. Biophys. Res. Commun. 2000, 269, 633-640), stress fibro-formation (Kimura et al. Science 1997, 275, 1308-1311; Yamashiro et al. J. Cell Biol. 2000, 150, 797-806), thrombotic disorders (Kikkawa et al. FEBS Lett. 2000, 466, 70-74; Bauer et al. Blood 1999 94, 1665-1672; Klages et al. J. Cell Biol. 1999, 144, 745-754; Retzer et al. Cell Signal 2000, 12, 645-648) and leukocyte aggregation (Kawaguchi et al. Eur. J. Pharmacol. 2000, 403, 203-208; Sanchez-Madrid et al. J. Immunol. 2003, 171, 1023-1034; Sanchez-Madrid, et al. J. Immunol. 2002, 168, 400-410) and bone resorption (Chellaiah et al. J. Biol. Chem. 2003, 278, 29086-29097), activation of the transport system Na / H exchange (Kawaguchi et al. Eur. J. Pharmacol. 2000, 403, 203-208), Alzheimer's disease (Zhou et al. Science 2003, 302, 1215-1217), activation of aducin (Fukata et al. J. Biol. Chem., 1998, 273, 5542-5548), and in SREB (a binding element of the sterol response), signaling and its effect on lipid metabolism (Lin et al. Circ. Res. 2003, 92, 1296-304).

As a result, a compound having an inhibitory effect on Rho kinase and / or Rho kinase-mediated phosphorylation of myosin light chain phosphatase is useful for the treatment and / or prevention of cardiovascular and non-cardiovascular diseases in which Rho kinase is involved as primary or secondary cause of the disease. These are diseases such as hypertension, pulmonary hypertension, eye hypertension, retinopathy and glaucoma, peripheral circulation disorder, peripheral arterial occlusion (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (terminal damage organs), pneumofibrosis, liver fibrosis, liver failure, nephropathy, including nephropathy induced by hypertension, not induced by hypertension and dia nephropathies, renal failure, kidney fibrosis, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebrovascular spasm, cerebral ischemia, pain, such as neuropathy , neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy sores, diabetes and diabetes complications, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS (AIDS), osteopathy such as osteoporosis, bacterial infections of the intestinal tract, sepsis, the development of cancer progression, for example, breast cancer glands, colon, prostate, ovaries, brain and lung and their metastases.

WO 2001/64238 describes isoquinoline-5-sulfonamide derivatives optionally substituted with - (CH ₂ ) _1-6 -O- (CH ₂ ) _0-6 -, - (CH ₂ ) _0-6 -S- (CH ₂ ) _0-6 - or a heterocyclic group attached through - (CH ₂ ) _0-6 -, applicable as neuroprotectors.

WO 2004/106325 (Schering AG) describes fasudil, a prodrug of an Rho kinase inhibitor containing an ester or ester group at position 1 of the isoquinoline ring.

WO 2001/039726 generally describes —O- (C ₀ -C ₁₀ ) alkyl heteroaryl substituted cyclohexyl derivatives useful for treating microbial infections.

JP 10087629 A describes isoquinoline derivatives useful for the treatment of diseases caused by Heliobacter pylori, such as, for example, gastric cancer or ulcer. Derivatives of isoquinoline can be substituted with an OH group at position 1 and preferably substituted with an X - [(C ₁ -C ₆ ) alkylene)] _0-1- Y group at position 5, where X can be oxygen and Y can be aryl or a heterocyclic group.

Hagihara et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) describe 6-benzyloxyisoquinoline for the treatment of infectious diseases caused by Heliobacter pylori.

US 5,480,883 generally discloses compounds of the formula “ArI — X — ArII,” wherein X may be (CHR ₁ ) _m —Z— (CHR ₁ ) _n , for example, Z — CH ₂ , where Z may be O; R ₁ represents hydrogen or alkyl; ArI may be, inter alia, optionally substituted isoquinolone; and ArII may be, inter alia, an optionally substituted C _3-7 monocyclic saturated heterocyclic system, such as EGF and / or PDGF receptor inhibitors, useful for inhibiting cell proliferation.

WO 2005/030791 (Merck & Co.) for the treatment of cardiac arrhythmia, stroke, congestive heart failure, and so on, generally describe isoquinolone derivatives as potassium channel inhibitors that are optionally substituted at position 6 by a group (CR ^e R ^f ) _p OR ⁴³ where p may be zero and R ⁴³ is, for example, a (C ₃ -C ₁₀ ) cycloalkyl radical optionally substituted with NR ⁵¹ R ⁵² , where R ⁵¹ and R ⁵² may be hydrogen, (C ₁ -C ₆ ) alkyl etc.; or R ⁴³ represents a group R ⁸¹ defined as a (4-6) membered unsaturated or saturated monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatoms; and at position 4, substituted by a directly attached optionally substituted aryl or heteroaryl ring.

WO 2005/030130 (Merck & Co.) generally describes, for the treatment of cardiac arrhythmias, stroke, congestive heart failure, and derivatives of isoquinoline as potassium channel inhibitors which, at position 1, can be substituted with hydroxyl; and at position 6, optionally substituted with a group (CR ^e R ^f ) _p OR ⁴³ , where p may be zero and R ⁴³ is, for example, a (C ₃ -C ₁₀ ) cycloalkyl radical optionally substituted with a group NR ⁵¹ R ⁵² , in wherein R ⁵¹ and R ⁵² may be hydrogen, (C ₁ -C ₆ ) alkyl, and so on; or R ⁴³ represents a group R ⁸¹ defined as a (4-6) membered unsaturated or saturated monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatoms; and at position 4, are substituted by a directly attached optionally substituted aryl or heteroaryl ring.

WO2003 / 053330 (Ube) generally describes isoquinolone derivatives of the formula

as Rho kinase inhibitors

WO2007 / 012422 (Sanofi-Aventis) generally describes isoquinoline and isoquinolone derivatives of the formula

as Rho kinase inhibitors.

WO2008 / 077555 and WO 2008/077556 (Sanofi-Aventis) also describe 6-substituted derivatives of isoquinoline and isoquinolone as Rho kinase inhibitors.

WO2007 / 039563 and WO 2008/020081 (Organon) describe 6-substituted isoquinoline derivatives as Rho kinase inhibitors.

Although several Rho kinase inhibitors have been described, there is still a need for additional compounds useful for the treatment of diseases mediated by Rho kinase.

An embodiment of the present invention is a compound of formula (I)

where R ₁ represents H, OH or NH ₂ ;

R ₃ represents H, halogen, CN, (C ₁ -C ₆ ) alkyl, OH, NH ₂ or NHR ′;

R ₄ represents H, halogen, hydroxy, CN, (C ₁ -C ₆ ) alkyl, R 'or (C ₁ -C ₆ ) alkylene-R';

R ₅ represents H, halogen, CN, (C ₁ -C ₆ ) alkyl or R ';

R ₇ represents H, halogen, CN, (C ₁ -C ₆ ) alkyl, O- (C ₁ -C ₆ ) alkyl, R ′ or SO ₂ —NH ₂ ;

R ₈ represents H, halogen or (C ₁ -C ₆ ) alkyl;

R ₆ is one (C ₁ -C ₄ ) alkylene attached to a cycloalkyl ring in which (C ₁ -C ₄ ) alkylene forms a second bond with another carbon atom of the cycloalkyl ring to form a bicyclic ring system,

where in a bicyclic ring system, one or two carbon atoms are substituted by a group independently selected from O, NR ₁₃ , S, SO, or SO ₂ ;

or, if m and s are 2, m is 3 and s is 1, or m is 4 and s is 0,

R ₆ represents a CH ₂ —CH- (CH ₂ ) ₂ group which, through one CH ₂ group, is connected to a cycloalkyl ring and the other two CH ₂ groups are attached to different carbon atoms of the cycloalkyl ring,

and if m is 3 and s is 3,

R ₆ represents two methylene groups attached to different carbon atoms of the cycloalkyl ring, where methylene groups or the CH ₂ —CH- (CH ₂ ) ₂ group are attached to the carbon atoms of the cycloalkyl ring and form an adamantane system of the formula

where L can be attached to any secondary or tertiary carbon atom,

or R ₆ together with R ₁₁ and the N atom form a (C ₃ -C ₈ ) heterocycloalkyl which forms a condensed system with a cycloalkyl radical or combines as a spirocyclic ring system to form a radical of the formula

where the bicyclic ring system or the adamantane system, or containing a (C ₃ -C ₈ ) heterocycloalkyl ring system is an unsubstituted or optionally substituted R ₉ group;

R ₉ represents

R ',

OH,

halogen,

(C ₁ -C ₆ ) alkyl,

O- (C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-R ',

(C ₂ -C ₆ ) alkenyl,

(C ₂ -C ₆ ) alkynyl,

(C ₁ -C ₆ ) alkylene-O-R ',

(C ₁ -C ₆ ) alkylene-CH [R '] ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) -R ',

(C ₁ -C ₆ ) alkylene-C (O) NH ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) NH-R ',

(C ₁ -C ₆ ) alkylene-C (O) NH- (C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-C (O) N [(C ₁ -C ₆ ) alkyl] ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) N [R '] ₂ ;

(C ₁ -C ₆ ) alkylene-C (O) O- (C ₁ -C ₆ ) alkyl,

COOH,

C (O) O- (C ₁ -C ₆ ) alkyl,

C (O) OR ',

C (O) (C ₁ -C ₆ ) alkyl,

C (O) R ',

CONH ₂ ,

C (O) -NH- (C ₂ -C ₆ ) alkenyl,

C (O) -NH- (C ₂ -C ₆ ) alkynyl,

C (O) -NH- (C ₁ -C ₆ ) alkyl,

C (O) NHR ',

C (O) -NH (C ₁ -C ₆ ) alkylene-R ',

C (O) N [(C ₁ -C ₆ ) alkyl] R ',

C (O) N [(C ₁ -C ₆ ) alkyl] ₂ ,

C (O) - (C ₁ -C ₆ ) alkylene-R 'or

C (O) O (C ₁ -C ₆ ) alkylene-R ';

R ₁₁ and R _{12 are} independently of one another

H

R ',

(C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-R ',

(C ₁ -C ₆ ) alkylene-O- (C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-O-R ',

(C ₁ -C ₆ ) alkylene-CH [R '] ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) -R ',

(C ₁ -C ₆ ) alkylene-C (O) NH ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) NH-R ',

(C ₁ -C ₆ ) alkylene-C (O) NH- (C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-C (O) N [(C ₁ -C ₆ ) alkyl] ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) N [R '] ₂ ,

(C ₁ -C ₆ ) alkylene-C (O) O- (C ₁ -C ₆ ) alkyl,

C (O) O- (C ₁ -C ₆ ) alkyl,

C (O) OR ',

C (O) (C ₁ -C ₆ ) alkyl,

C (O) R ',

C (O) NH- (C ₁ -C ₆ ) alkyl,

C (O) NHR ',

C (O) N [(C ₁ -C ₆ ) alkyl] R ',

C (O) N [(C ₁ -C ₆ ) alkyl] ₂ ,

C (O) - (C ₁ -C ₆ ) alkylene-R ',

C (O) O (C ₁ -C ₆ ) alkylene-R 'or

R ₁₁ and R ₁₂ , together with the N atom to which they are attached, form a (C ₃ -C ₈ ) heterocycloalkyl;

R ₁₃ represents H or (C ₁ -C ₆ ) alkyl;

n is 0, 1, 2, 3 or 4;

m is 1, 2, 3 or 4;

s is 0, 1, 2 or 3;

L is O (CH ₂ ) _p , S (CH ₂ ) _p , S (O) (CH ₂ ) _p , SO ₂ (CH ₂ ) _p , NH (CH ₂ ) _p , N (C ₁ -C ₆ ) alkyl- (CH ₂ ) _p , N (C ₃ -C ₆ ) cycloalkyl- (CH ₂ ) _p or N [(C ₁ -C ₃ ) alkylene-R '] - (CH ₂ ) _p ;

p is 0, 1, 2, 3 or 4;

R 'represents

(C ₃ -C ₈ ) cycloalkyl,

(C ₅ -C ₁₀ ) heteroaryl,

(C ₃ -C ₈ ) heterocycloalkyl,

(C ₆ -C ₁₀ ) aryl;

where in the residues R ₃ -R _13, alkyl or alkylene is unsubstituted or optionally substituted one or more times by the group OH, OCH ₃ , C (O) OH, C (O) OCH ₃ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , C (O) NH ₂ , C (O) NHCH ₃ or C (O) N (CH ₃ ) ₂ ;

where in the residues R ₃ -R ₁₃ cycloalkyl or heterocycloalkyl is unsubstituted or optionally one or more times substituted by (C ₁ -C ₆ ) alkyl, halogen, OH, OCH ₃ , C (O) OH, C (O) OCH ₃ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , C (O) NH ₂ , C (O) NHCH ₃ or C (O) N (CH ₃ ) ₂ ;

where in the residues R ₃ -R ₁₃ alkyl or alkylene is unsubstituted or optionally substituted one or more times by halogen;

where in the residues R ₃ -R ₁₃ (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl are unsubstituted or optionally substituted one or more times by a group independently selected from halogen, OH, NO ₂ , N ₃ , CN, C (O) - (C ₁ -C ₆ ) alkyl, C (O) - (C ₆ -C ₁₀ ) aryl, C (O) OH, C (O) O (C ₁ -C ₆ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₆ ) alkyl, C (O) N [(C ₁ -C ₆ ) alkyl] ₂ , (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-NH (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-N [(C ₁ -C ₆ ) alkyl] ₂ , (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, O- (C ₁ -C ₆ ) alkyl, OC (O) - (C ₁ -C ₆ ) alkyl, PO ₃ H ₂ , SO ₃ H, SO _2- NH ₂ , SO ₂ NH (C ₁ -C ₆ ) alkyl, SO ₂ N [(C ₁ -C ₆ ) alkyl] ₂ , S- (C ₁ -C ₆ ) alkyl, SO- (C ₁ -C ₆ ) alkyl, SO ₂ - (C ₁ -C ₆ ) alkyl, SO ₂ —N = CH — N [(C ₁ -C ₆ ) alkyl] ₂ , SF ₅ , C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N [(C ₁ -C ₆ ) alkyl] ₂ , NH-C (O) - (C ₁ -C ₆ ) alkyl, NH-C (O) O- (C ₁ -C ₆ ) alkyl, NH-SO ₂ - (C ₁ -C ₆ ) alkyl, NH-SO ₂ - (C ₆ -C ₁₀ ) aryl, NH-SO ₂ - (C ₅ -C ₁₀ ) heteroaryl, NH-SO ₂ - (C ₃ -C ₈ ) heterocycloalkyl, N ( C ₁ -C ₆ ) alkyl-C (O) - (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) alkyl-C (O) O- (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) alkyl-C (O) -NH- (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl, O- (C ₆ -C ₁₀ ) aryl, O- (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl, ( C ₁ -C ₆ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl, (C ₁ -C ₆ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl, O- (C ₁ -C ₆ ) alkylene- (C ₅ - C ₁₀ ) heteroaryl, O- (C ₁ -C ₆ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl,

where (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl or (C ₃ -C ₈ ) cycloalkyl may be substituted one to three times by a group independently selected from halogen , OH, NO ₂ , CN, O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH ₂ , NH (C ₁ -C ₆ ) alkyl, N [(C ₁ -C ₆ ) alkyl] ₂ , SO ₂ CH ₃ , C (O) OH, C (O) O- (C ₁ -C ₆ ) alkyl, C (O) NH ₂ , (C ₁ -C ₆ ) alkylene-O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-O- (C ₆ -C ₁₀ ) aryl or O- (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl;

or where (C ₆ -C ₁₀ ) aryl is a vicinally substituted O- (C ₁ -C ₄ ) alkylene-O group, whereby forms a (5-8) membered ring together with the carbon atoms to which the oxygen atoms are attached ;

and where the aryl substituents of the (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl and (C ₃ -C ₈ ) cycloalkyl groups cannot be further substituted with an aryl, heteroaryl- a heterocycloalkyl or cycloalkyl group;

their stereoisomeric and / or tautomeric forms and / or their pharmaceutically acceptable salts.

In yet another embodiment, the present invention also relates to a compound of formula (I) and / or a pharmaceutically acceptable salt thereof for use as a medicine. The invention also relates to the use of at least one compound of formula (I) and / or a pharmaceutically acceptable salt thereof for the treatment and / or prophylaxis of Rho kinase-mediated diseases such as hypertension, pulmonary hypertension, eye hypertension, retinopathy, glaucoma, disorder peripheral circulation, occlusive peripheral artery disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, coronary heart disease, ischemic organ failure terminal organs), pneumofibrosis, liver fibrosis, liver failure, nephropathy, renal failure, kidney fibrosis, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, vascular disorders, brain, cerebral ischemia, pain, neuronal degeneration, spinal cord damage, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunction, art heriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS (AIDS), osteopathy, infectious diseases of the intestinal tract caused by bacteria, the development and progression of sepsis or cancer. The invention also relates to a medicament containing an effective amount of at least one compound of formula (I) and / or its pharmacologically acceptable salt. Another objective of the present invention is a method for producing a compound of formula (I).

The term “alkyl” as used in the expressions (C ₁ -C ₂ ) alkyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₆ ) alkyl and in the corresponding alkylene substituents, is understood as a hydrocarbon residue, which may be linear, that is, a straight or branched chain and contains 1, 2, 3, 4, 5, or 6 carbon atoms, respectively. This also applies when the alkyl group occurs as a substituent in another group, for example, in an alkoxy group (O-alkyl), S-alkyl or in the group-O (C ₁ -C ₆ ) alkylene-O-, alkoxycarbonyl group or an arylalkyl group . Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. Alkyl or alkylene groups may optionally be halogenated one or more times, for example, alkyl groups may be fluorinated, for example perfluorinated. Examples of halogenated alkyl groups are CH ₂ F, CHF ₂ , CF ₃ and CH ₂ CF ₃ , OCF ₃ , SCF ₃ or —O- (CF ₂ ) ₂ —O—.

The term “(C ₂ -C ₆ ) alkenyl” means a hydrocarbon residue having a straight or branched carbon chain, which contains 2-6 carbon atoms and has, depending on the length of the chain, 1, 2 or 3 double bonds, for example vinyl, 1-propenyl, 2-propenyl (= allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl. The double bond may, where possible, have an E or Z orientation. Double bonds can be either internal or terminal.

(C ₂ -C ₆ ) -alkynyl groups are a straight or branched chain hydrocarbon residue which contains 2-6 carbon atoms and has, depending on the chain length, 1 or 2 triple bonds, for example ethynyl, 1-propynyl , 2-propynyl (= propargyl) or 2-butynyl. Triple bonds can be either internal or terminal.

The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term “(C ₁ -C ₈ ) heteroalkyl or corresponding (C ₁ -C ₈ ) heteroalkylene substituents” is understood to mean (C ₁ -C ₈ ) alkyl or (C ₁ -C ₈ ) alkylene groups in which at least one carbon atom, preferably one or two carbon atoms and, more preferably, one carbon atom represents a substituted group selected from O, NH or S, and where the nitrogen and sulfur atoms may optionally be oxidized. The heteroatom may be at any position in the alkyl or alkylene group. Examples of (C ₁ -C ₈ ) heteroalkyl groups include —CH ₂ —O — CH ₃ , —CH ₂ —CH ₂ —O — CH ₂ —CH ₃ , —CH ₂ —NH — CH ₂ —CH ₃ , - CH ₂ -N (CH ₂ -CH ₃ ) ₂ , -CH ₂ -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -O-CH (CH ₃ ) ₂ , —CH ₂ —O — CH ₂ —CH ₂ —O — CH ₃ or O — CH ₂ —CH ₃ .

(C ₃ -C ₈ ) cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6, 7 or 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. They may also be substituted and / or may contain 1 or 2 double bonds (unsaturated cycloalkyl groups), for example cyclopentenyl or cyclohexenyl, which may be attached to any carbon atom.

The term “(C ₆ -C ₁₀ ) aryl group” means an aromatic ring or a cyclic system that contains two aromatic rings that are fused or otherwise connected, or that contains two fused aromatic rings, where one ring is saturated or partially saturated that is, it contains at least one single CC bond, for example, phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha or beta tetralon, indanyl or indan-1-onyl group. A preferred (C ₆ -C ₁₀ ) aryl group is phenyl.

The term “(C ₃ -C ₈ ) heterocycloalkyl group” means a saturated (not containing double bonds) monocyclic carbon ring system containing 3, 4, 5, 6, 7, or 8 ring atoms, in which one or more carbon atoms can be substituted one or more heteroatoms, such as, for example, 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or a combination of different heteroatoms. Heterocycloalkyl residues can be joined at any position, for example, position 1, position 2, position 3, position 4, position 5, position 6, position 7, or position 8. The corresponding N-oxides, sulfoxides, or sulfones of these compounds are also included.

Examples of (C ₃ -C ₈ ) heterocycloalkyl groups are oxiranyl, oxetanyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, for example 1,3-dioxolanyl, dioxanyl, for example, 1,4-dioxanyl, piperidinyl, pyrrolidinyl, imidazolidinyl diryl triaz , piperazinyl, triazinanyl, for example, 1,3,5-triazinanyl, 1,2,3-triazinanyl or 1,2,4-triazinanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dithiolanyl, for example, 1,3-dithiolanyl, dithianil, thiazolidinyl, oxazolidinyl oxathiolanyl, e.g. 1,3-oxathiolanyl, morphols yl or thiomorpholinyl, diazepanyl, e.g., 1,4-diazepanyl.

A preferred (C ₃ -C ₈ ) heterocycloalkyl group is morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxetanyl or tetrahydropyranyl.

The term “(C ₅ -C ₁₀ ) heteroaryl” means a mono- or bicyclic ring system where one or more carbon atoms can be substituted with one or more heteroatoms, such as, for example, 1, 2, 3 or 4 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or combinations of different heteroatoms. Heteroaryl residues can be joined at any position, for example, at position 1, position 2, position 3, position 4, position 5, position 6, position 7 or position 8. (C ₅ -C ₁₀ ) heteroaryl groups can be (1) an aromatic monocyclic or bicyclic ring system or (2) a bicyclic ring system, where one ring is aromatic and the second ring is at least partially saturated.

Also included are the corresponding N-oxides, sulfoxides or sulfones of these compounds.

Suitable (C ₅ -C ₁₀₎ heteroaryl groups are benzimidazolyl, benzofuryl, benzothienyl, azaindolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbolinyl, cinnolinyl, chromanyl, chromenyl, naphthyridinyl, phthalazinyl, pyridoimidazoles, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, indolicinyl, indolyl, furyl, furazanyl, thienyl, imidazolyl, imidazolinyl, 1H-indazolyl, oxazolazi, pyrazole zolyl, 1,2,4-oxydiazolyl, 1,2,5-oxydiazolyl, 1,3,4-oxydiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolinyl, pyrrolyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl.

The term “pyridyl” means both 2-, 3-, and 4-pyridyl. The term "thienyl" means both 2- and 3-thienyl. The term “furyl” means both 2- and 3-furyl. Also included are the corresponding N-oxides of these compounds, for example 1-hydroxy-2-, 3- or 4-pyridyl.

Substitutions in (C ₅ -C ₁₀ ) heteroaryl residues can occur at free carbon atoms or at nitrogen atoms.

Preferred examples of (C ₅ -C ₁₀ ) heteroaryl residues are benzofuryl, quinolinyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, triazolyl, oxdiazolyl, pyrazinyl, pyrimidinyl, pyrimidinyl and pyrimidinyl.

A preferred (C ₅ -C ₁₀ ) heteroaryl is a (C ₅ -C ₆ ) heteroaryl group. Preferred (C ₅ -C ₆ ) heteroaryl residues are furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, triazolyl, oxdiazolyl, pyrazinyl, pyrimidinyl and pyridazinyl. Preferred examples of (C ₅ -C ₆ ) heteroaryl residues are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5 -yl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2- or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl , 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl or pyrazinyl.

In the residues R ₃ -R ₁₃ (C ₆ -C ₁₀ ), aryl and (C ₅ -C ₁₀ ) heteroaryl residues are unsubstituted or, unless otherwise indicated, are optionally substituted one or more times, preferably one to three times a group independently selected from

halogen, OH, NO ₂ , N ₃ , CN, C (O) - (C ₁ -C ₆ ) alkyl, C (O) - (C ₆ -C ₁₀ ) aryl, C (O) OH, C (O) O (C ₁ -C ₆ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₆ ) alkyl, C (O) N [(C ₁ -C ₆ ) alkyl] ₂ , (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-NH (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-N [(C ₁ - C ₆ ) alkyl] ₂ , (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, O- (C ₁ -C ₆ ) alkyl, OC (O) - (C ₁ -C ₆ ) alkyl, PO ₃ H ₂ , SO ₃ H, SO ₂ -NH ₂ , SO ₂ NH (C ₁ -C ₆ ) alkyl, SO ₂ N [(C ₁ -C ₆ ) alkyl] ₂ , S- (C ₁ -C ₆ ) alkyl, SO- (C ₁ -C ₆ ) alkyl, SO ₂ - (C ₁ -C ₆ ) alkyl, SO ₂ -N = CH-N [(C ₁ -C ₆ ) alkyl] ₂ , SF ₅ , C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N [(C ₁ -C ₆ ) alkyl] ₂ , NH-C (O) - (C ₁ -C ₆ ) alkyl , NH-C (O) O- (C ₁ -C ₆ ) alkyl, NH-SO ₂ - (C ₁ -C ₆ ) alkyl, NH-SO ₂ - (C ₆ -C ₁₀ ) aryl, NH-SO ₂ - (C ₅ -C ₁₀ ) heteroaryl, NH-SO ₂ - (C ₃ -C ₈ ) heterocycloalkyl, N (C ₁ -C ₆ ) alkyl-C (O) - (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) alkyl-C (O) O- (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) alkyl-C (O) -NH- (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl, O- (C ₆ -C ₁₀ ) aryl, O- (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl, (C ₁ -C ₆ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl, (C ₁ -C ₆ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl, O- ( C ₁ -C ₆ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl; O- (C ₁ -C ₆ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl;

wherein said (C ₆ -C ₁₀ ) aryl or (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl or (C ₃ -C ₈ ) cycloalkyl may be substituted one to three times by a group independently selected from halogen, OH, NO ₂ , CN, O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH ₂ , NH (C ₁ -C ₆ ) alkyl, N [(C ₁ -C ₆ ) alkyl] ₂ , SO ₂ CH ₃ , C (O) OH, C (O) O- (C ₁ -C ₆ ) alkyl, C (O) NH ₂ , (C ₁ -C ₆ ) alkylene-O- ( C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-O- (C ₆ -C ₁₀ ) aryl or O- (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl;

or where (C ₆ -C ₁₀ ) aryl is a vicinally substituted O- (C ₁ -C ₄ ) alkylene-O group, thereby forming, together with the carbon atoms to which the oxygen atoms are attached, a (5-8) membered ring ;

and where the aryl substituents of the (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl or (C ₃ -C ₈ ) cycloalkyl groups cannot be further substituted with an aryl group, heteroaryl, heterocycloalkyl or cycloalkyl.

Preferred substituents for the (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl groups are OH, (C ₁ -C ₄ ) alkyl, O- (C ₁ -C ₄ ) alkyl, O-phenyl, phenyl , C (O) O- (C ₁ -C ₆ ) alkyl, C (O) OH, C (O) - (C ₁ -C ₄ ) alkyl, halogen, NO ₂ , SO ₂ NH ₂ , CN, SO ₂ - (C ₁ -C ₄ ) alkyl, SO ₂ -N = CH-N [(C ₁ -C ₆ ) alkyl] ₂ , NH-SO ₂ - (C ₁ -C ₄ ) alkyl, NH ₂ , NH-C (O) - (C ₁ -C ₄ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkyl-OH, C (O) N [(C ₁ -C ₄ ) alkyl] ₂ , CONH (C ₁ -C ₆ ) alkyl, C (O) NH ₂ , N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkylene-N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkylene-O- (C ₁ -C ₄ ) alkyl, (C ₅ -C ₆ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl, (C ₁ -C ₄ ) alkylene- ( C ₆ -C ₁₀₎ aryl, wherein (C ₆ -C ₁₀₎ aryl may be further from one to tre substituted once, preferably once, by halogen, (C ₁ -C ₄₎ alkyl, O- (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkylene-O- (C ₁ -C ₆₎ alkyl, ( C ₆ -C ₁₀ ) aryl, O- (C ₁ -C ₆ ) alkylene- (C ₆ -C ₁₀ ) aryl, or may be vicinally substituted with O- (C ₁ -C ₄ ) alkylene-O, thereby forming together with carbon atoms attached to oxygen atoms, (5-8) -membered cycle.

More preferred substituents for (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl are OH, halogen, CN, phenyl, O-phenyl, NH-C (O) - (C ₁ -C ₄ ) alkyl , C (O) - (C ₁ -C ₄ ) alkyl, C (O) -O (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyl, O- (C ₁ -C ₄ ) alkyl, CONH ₂ , SO ₂ -NH ₂ , SO ₂ - (C ₁ -C ₄ ) alkyl or SO ₂ -N = CH-N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkylene phenyl, (C ₁ -C ₄ ) alkylene-O- (C ₁ -C ₄ ) alkyl or (C ₅ -C ₆ ) heteroaryl, where phenyl is unsubstituted or optionally one to three times substituted, preferably once, by an OH group, halogen, (C ₁ -C ₄ ) alkyl or O- (C ₁ -C ₄ ) alkyl.

Even more preferred substituents for (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl are OH, halogen, CN, phenyl, O-phenyl, NH-C (O) - (C ₁ -C ₄ ) alkyl, especially NH-C (O) -CH ₃ ; C (O) - (C ₁ -C ₄ ) alkyl, especially C (O) -CH ₃ ; C (O) -O (C ₁ -C ₄ ) alkyl, especially C (O) -OCH ₃ ; (C ₁ -C ₄ ) alkyl, especially CH ₃ or CF ₃ ; O- (C ₁ -C ₄ ) alkyl, especially O-CH ₃ ; CONH ₂ , SO ₂ —NH ₂ , SO ₂ - (C ₁ -C ₄ ) alkyl, especially SO ₂ —CH ₃ or SO ₂ —CF ₃ ; or SO ₂ —N = CH — N [(C ₁ -C ₄ ) alkyl] ₂ , especially SO ₂ —N = CH — N [(CH ₃ ) _2,

where phenyl is unsubstituted or one to three times optionally substituted, preferably once, by OH, halogen, (C ₁ -C ₄ ) alkyl or O- (C ₁ -C ₄ ) alkyl.

Particularly preferred substituents for the (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl groups are OH, CN, (C ₁ -C ₄ ) alkyl, especially CH ₃ or CF ₃ ; O (C ₁ -C ₄ ) alkyl, especially O-CH ₃ ; halogen or phenyl; where phenyl may be further one to three times substituted, preferably once, by OH, halogen, (C ₁ -C ₄ ) alkyl, especially CH ₃ or CF ₃ ; or O- (C ₁ -C ₄ ) alkyl, especially O-CH ₃ .

The most preferred substituents for the (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₁₀ ) heteroaryl groups are OH, CN, halogen, (C ₁ -C ₄ ) alkyl, especially CH ₃ or CF ₃ , O (C ₁ —C ₄ ) alkyl, especially O — CH ₃ or halogen.

In monosubstituted phenyl groups, the substituent may be in position 2, position 3 or position 4, with position 3 and position 4 being preferred. If the phenyl group has two substituents, they may be in positions 2,3, positions 2,4, positions 2,5, positions 2,6, positions 3,4 or positions 3,5. In phenyl groups having three substituents, the substituents may be in positions 2,3,4, positions 2,3,5, positions 2,3,6, positions 2,4,5, positions 2,4,6 or positions 3, 4,5.

The above statements regarding phenyl groups respectively apply to divalent groups formed from phenyl groups, i.e. phenylene groups, which may be unsubstituted phenylene or substituted 1,2-phenylene, 1,3-phenylene or 1,4-phenylene . The above statements also apply accordingly to aryl subgroups in arylalkylene groups. Examples of arylalkylene groups, which may also be unsubstituted or substituted at the aryl subgroup, as well as at the alkylene subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenylpropylene.

In the radicals R _{3 to} R _13, alkyl or alkylene is unsubstituted or, unless otherwise specified, optionally substituted one or more times with halogen. When substituted, the alkyl or alkylene is preferably one to three times substituted with a halogen selected from chlorine or bromine, but may be substituted one or more times with fluorine, for example, being perfluorinated. Preferably, the halogen is fluoro. Preferably, when alkylene is non-halogenated. More preferably, the alkyl or alkylene is non-halogenated.

In the radicals R _{3 to} R _13, alkyl or alkylene is unsubstituted or, unless otherwise specified, optionally substituted one or more times by a group independently selected from OH, OCH ₃ , COOH, COOCH ₃ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , CONH ₂ , CONHCH ₃ or CON (CH ₃ ) ₂ . When substituted, the number of substituents is preferably between 1, 2, 3 or 4, more preferably 1 or 2, with 1 being even more preferred. Preferably, when alkylene is not substituted with one of these groups. More preferably, when alkyl or alkylene is not substituted with one of these groups. Preferably, the alkyl or alkylene in residues R ₃ , R ₄ , R ₅ , R ₇ and R _{8 is} not substituted. In a further embodiment, the alkyl or alkylene in residues R ₄ , R ₅ , R ₇ and R ₈ -R _{14 is} not substituted with one of these groups.

In the radicals R ₃ -R _13, cycloalkyl or heterocycloalkyl is unsubstituted or, unless otherwise specified, optionally one or more times substituted by (C ₁ -C ₆ ) alkyl, halogen, OH, OCH ₃ , COOH, COOCH ₃ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , CONH ₂ , CONHCH _3, or CON (CH ₃ ) ₂ .

In substitution, the number of substituents is preferably between 1, 2, 3 or 4, more preferably 1 or 2, with 1 being even more preferred. Preferably, when cycloalkyl or heterocycloalkyl in residues R ₃ , R ₄ , R ₅ , R ₇ and R _{9 are} not substituted. In a further embodiment, cycloalkyl or heterocycloalkyl at residues R ₃ -R _{13 is} not substituted. In a preferred embodiment, heterocycloalkyl is not substituted. In yet another embodiment, cycloalkyl is not substituted.

The usual and preferred substituents of the (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl and (C ₃ -C ₈ ) cycloalkyl groups indicated above can be combined with conventional and preferred the definitions for R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₁ , R ₁₂ , R ₁₃ , n, s, m, p and L described in the following embodiments compounds of formula (I).

The following embodiments of the compound of formula (I) do further characterize it and are part of the present invention.

In one embodiment of a compound of formula (I), R ₁ is H, and the compound is defined by formula (II)

In yet another embodiment of the present invention, R ₁ is OH, and the compound describes the formula (IIIa)

An isoquinoline derivative of formula (I), wherein R ₁ is OH, includes the corresponding tautomeric derivative of 1-isoquinolone, which is characterized by formula (IIIb)

This tautomeric form also represents an embodiment of the present invention.

In a further embodiment, R ₁ is NH ₂ and the compound is characterized by formula (IV)

The following further embodiments equally apply to the compounds of formulas (I), (II), (IIIa), (IIIb) and (IV).

In a preferred embodiment, R ₁ is H or OH; more preferably when R ₁ is OH.

In one embodiment, R _{3 is} preferably H, halogen, (C ₁ -C ₆ ) alkyl or NH-R ′. In another more preferred embodiment, R ₃ is H, halogen, unsubstituted or substituted NH- (C ₅ -C ₆ ) heteroaryl, unsubstituted or substituted NH- (C ₃ -C ₈ ) heterocycloalkyl, or unsubstituted or substituted NH-phenyl . In an even more preferred embodiment, R ₃ is unsubstituted or substituted NH- (C ₅ -C ₆ ) heteroaryl containing one or more N atoms, or unsubstituted or substituted NH-phenyl. In a most preferred embodiment, R ₃ is H.

Examples of substituents NHR 'in R ₃ are

An asterisk (*) indicates the attachment of a bond to the C-atom of the ring.

In a preferred embodiment, R ₄ is H, halogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₂ ) phenyl. In a more preferred embodiment, R ₄ is H, halogen or unsubstituted or substituted (C ₁ -C ₄ ) alkyl or (C ₁ -C ₂ ) phenyl, preferably unsubstituted (C ₁ -C ₄ ) alkyl or (C ₁ -C ₂ ) phenyl. Most preferably, R ₄ is H.

In a preferred embodiment, R ₅ is H, CN, halogen, unsubstituted or substituted (C ₁ -C ₆ ) alkyl, unsubstituted or substituted (C ₆ -C ₁₀ ) aryl or unsubstituted or substituted (C ₅ -C ₁₀ ) heteroaryl . Examples R ₅ is hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, phenyl, thienyl or pyridyl, nitrile, (p-methoxy) phenyl, N-aniline, cyclopropyl, tetrazole, 4-methoxyaniline. In a more preferred embodiment, (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl or (C ₅ -C ₁₀ ) heteroaryl are unsubstituted. In an even more preferred embodiment, R ₅ is H, halogen, methyl, ethyl, phenyl, thienyl or pyridyl, more specifically H, halogen, methyl or ethyl. Most preferably, when R ₅ represents H.

In a preferred embodiment, R ₇ is H, halogen, nitrile, unsubstituted or substituted (C ₁ -C ₆ ) alkyl, unsubstituted or substituted O- (C ₁ -C ₆ ) alkyl, or unsubstituted or substituted R '. In a more preferred embodiment, R ₇ is H, halogen, nitrile, unsubstituted or substituted (C ₁ -C ₄ ) alkyl, unsubstituted or substituted O- (C ₁ -C ₄ ) alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted (C ₅ -C ₆ ) heteroaryl or unsubstituted or substituted (C ₃ -C ₆ ) cycloalkyl. Preferably, when the (C ₁ -C ₆ ) alkyl, phenyl or (C ₅ -C ₆ ) heteroaryl are unsubstituted.

In an even more preferred embodiment, R ₇ is H, fluoro, chloro, bromo, methyl, ethyl, methoxy, phenyl, nitrile, cyclopropyl or thienyl. More preferably, when R ₇ is H, fluoro, chloro, bromo, methyl or methoxy, in particular H or chloro. Most preferably, when R ₇ is chlorine.

In a preferred embodiment, R ₈ is H, Cl, F, methyl or ethyl. In a more preferred embodiment, R ₈ is H.

In a preferred embodiment, R ₉ is R ', OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-R', (C ₂ -C ₆ ) alkenyl, (C ₁ - C ₆ ) alkylene-C (O) NH-R ', (C ₁ -C ₆ ) alkylene-C (O) NH- (C ₁ -C ₆ ) alkyl, COOH, CONH ₂ , C (O) NH- ( C ₁ -C ₆ ) alkyl, C (O) NHR ', C (O) -NH- (C ₁ -C ₆ ) alkynyl, C (O) -NH (C ₁ -C ₆ ) alkylene-R' or C (O) N [(C ₁ -C ₆ ) alkyl] ₂ , where alkyl, alkylene and R 'are unsubstituted or substituted.

In a more preferred embodiment, R ₉ is OH, halogen, (C ₁ -C ₆ ) alkyl, R ', (C ₁ -C ₆ ) alkylene-R', (C ₂ -C ₆ ) alkenyl, COOH, CONH ₂ , C (O) NH- (C ₁ -C ₆ ) alkyl, C (O) NHR 'or C (O) N [(C ₁ -C ₆ ) alkyl] ₂ , where alkyl, alkylene and R' are unsubstituted or substituted.

More preferably, when R ₉ is OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, COOH, CONH ₂ , O-CH ₃ , phenyl, (C ₅ -C ₆ ) heteroaryl , (C ₃ -C ₈ ) heterocycloalkyl, (C ₁ -C ₂ ) alkylene phenyl, (C ₃ -C ₈ ) cycloalkyl, where alkyl, phenyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₆ ) heteroaryl or (C ₃ -C ₈ ) heterocycloalkyl are unsubstituted or substituted. Even more preferably, when R ₉ is OH, halogen, (C ₁ -C ₆ ) alkyl, COOH, CONH ₂ , O-CH ₃ , phenyl, (C ₁ -C ₂ ) alkylene phenyl, (C ₃ -C ₈ ) cycloalkyl wherein alkyl, phenyl or (C ₃ -C ₈ ) cycloalkyl is unsubstituted or substituted.

Most preferably, R ₉ is allyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethylene, isopropyloxymethylene, tetrahydrofuranyl, tetrahydropyranyl, phenyl or benzyl.

R ₉ may be attached to any carbon atom of the ring, including the attachment position of the linker group L.

,

,

,

,

,

,

,

.As examples of these embodiments of the invention, R ₉ is methyl, ethyl, propyl, isopropyl, phenyl,

,

,

,

,

,

,

,

.

An asterisk (*) indicates the attachment of a bond to the C-atom of the ring.

In one embodiment, the compounds of formula (I) R ₁₁ and R ₁₂ independently from each other are

H

R ',

(C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-R ',

(C ₁ -C ₆ ) alkylene-O- (C ₁ -C ₆ ) alkyl,

(C ₁ -C ₆ ) alkylene-O-R ',

C (O) NH- (C ₁ -C ₆ ) alkyl,

C (O) NHR ',

C (O) N [(C ₁ -C ₆ ) alkyl] ₂ ,

where R ', (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkylene are unsubstituted or substituted.

In a preferred embodiment, the compounds of formula (I) R ₁₁ and R ₁₂ independently from each other are

H

(C ₁ -C ₆ ) alkyl,

(C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₆ -C ₁₀ ) aryl,

(C ₁ -C ₄ ) alkylene-O- (C ₁ -C ₆ ) alkyl,

C (O) NH- (C ₁ -C ₆ ) alkyl, or

R ₁₁ and R ₁₂ , together with the N atom to which they are attached, form a (C ₃ -C ₈ ) heterocycloalkyl group,

where (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkylene, (C ₅ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) heterocycloalkyl, (C ₆ - C ₁₀ ) aryl are unsubstituted or substituted.

Preferably, the heterocyclyl group formed at R ₁₁ and R ₁₂ is morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl. More preferably, the heterocyclyl group is morpholinyl or piperazinyl.

In a more preferred embodiment of the compound of formula (I), R ₁₁ is H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) cycloalkyl; and

R ₁₂ represents

H

(C ₁ -C ₆ ) alkyl,

(C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₆ -C ₁₀ ) aryl,

(C ₁ -C ₄ ) alkylene-O- (C ₁ -C ₆ ) alkyl or

C (O) NH- (C ₁ -C ₆ ) alkyl.

where (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkylene, (C ₃ -C ₈ ) heterocycloalkyl, (C ₆ -C ₁₀ ) aryl are unsubstituted or substituted .

In an even more preferred embodiment, the compounds of formula (I)

R ₁₁ represents H or (C ₁ -C ₆ ) alkyl, and

R ₁₂ represents

H

(C ₁ -C ₆ ) alkyl,

(C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) cycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₅ -C ₁₀ ) heteroaryl,

(C ₁ -C ₄ ) alkylene- (C ₃ -C ₈ ) heterocycloalkyl,

(C ₁ -C ₄ ) alkylene- (C ₆ -C ₁₀ ) aryl or

(C ₁ -C ₄ ) alkylene-O- (C ₁ -C ₆ ) alkyl,

where (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkylene, (C ₃ -C ₈ ) heterocycloalkyl, (C ₆ -C ₁₀ ) aryl are unsubstituted or substituted .

More preferably, when R ₁₁ represents H, (C ₁ -C ₆ ) alkyl, and

R ₁₂ represents H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, where (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl are unsubstituted or substituted, preferably represent unsubstituted.

In a further embodiment, R ₁₁ is H, and

R ₁₂ represents H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl,

where (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl are unsubstituted.

Most preferably, when R ₁₁ and R ₁₂ represents H.

As examples for the previously mentioned embodiments of the invention, R ₁₁ or R ₁₂ independently of one another is hydrogen, methyl, ethyl, propyl, isopropyl, 3-methylbutyl, 2-methylpropyl, butyl, pentyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or a substituent selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

,

,

.

,

,

,

,

,

,

,

,

,

,

,

,

,

.

An asterisk (*) indicates the attachment of a bond to the N-atom of the amine.

In one embodiment, R ₁₃ is H or (C ₁ -C ₆ ) alkyl, which is unsubstituted or optionally substituted. More preferably, R ₁₃ is H or (C ₁ -C ₄ ) alkyl, most preferably H. Preferably, alkyl is unsubstituted.

In one embodiment of the compound of formula (I), the bicycle formed with R ₆ is selected from the group

или

or

which is unsubstituted or optionally substituted with R ₉ .

(the dotted line to the N atom indicates the position of the residue NR ₁₁ R ₁₂ )

In yet another embodiment, the compounds of formula (I) adamantane formed with R ₆ are selected from the group

which is unsubstituted or optionally substituted with residues R ₉ .

Preferably, the bicycle or adamantane is unsubstituted (n is 0).

In one embodiment, the adamantane formed has the following structure:

,

,

,

или

,

,

,

or

which is unsubstituted or optionally substituted with residues R ₉ .

A preferred embodiment of the adamantane formed with R ₆ is a residue of the formula

Particular embodiments for this residue correspond to the formula

,

или

.

,

or

.

Cis and trans isomers in adamantane residues, such as, for example, in structures

и

включены.

and

included.

In yet another embodiment, R ₆ together with R ₁₁ or R ₁₂ and an N atom form a (C ₃ -C ₈ ) heterocycloalkyl that forms a fused system with a cycloalkyl radical or combines as a spirocyclic ring system to form a radical of the formula

wherein said ring system is unsubstituted or optionally substituted with R ₉ residues.

Examples of residues formed using R ₆ and R ₁₁ are

In one embodiment, m is 2 and s is 2. In another embodiment, m is 3 and s is 1.

In a further embodiment, m is 2 and s is 1. In yet another embodiment, m is 3 and s is 0. And in yet another embodiment, m is 4 and s is 0.

In one embodiment of a compound of formula (I), n is 0, 1, or 2. More preferably, n is 0 or 1. Most preferably, n is 0.

In another embodiment, L is O (CH ₂ ) _p . In a further embodiment, L is S (CH ₂ ) _p , S (O) (CH ₂ ) _p or SO ₂ (CH ₂ ) _p . In yet another embodiment, L is NH (CH ₂ ) _p , N [(C ₁ -C ₆ ) alkyl] (CH ₂ ) _p , N [(C ₃ -C ₆ ) cycloalkyl] (CH ₂ ) _p , N [(C ₁ -C ₃ ) alkylene aryl] (CH ₂ ) _p or N [(C ₁ -C ₃ ) alkylene- (C ₅ -C ₆ ) heteroaryl] (CH ₂ ) _p , with NH (CH ₂ ) _p , N (C ₁ -C ₆ ) alkyl- (CH ₂ ) _p is more preferred. Preferred N (C ₁ -C ₆ ) alkyl is N (C ₁ -C ₄ ) alkyl, more preferably NCH ₃ or NCH ₂ CH ₃ , with NCH ₃ being more preferred. In a preferred embodiment, L is O (CH ₂ ) _p . In another preferred embodiment, L is S (CH ₂ ) _p . In a further embodiment, L is NH (CH ₂ ) _p . Most preferably, L represents an O, S or NH atom, with an O atom being particularly preferred.

Preferably, p is 0, 1, 2 or 3, more preferably 0 or 1, with 0 being most preferred.

More preferably, L is O, S or NH, preferably L is O.

In a further embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of

6- (4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-allyl-4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-amino-4-propyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-amino-4-methyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-amino-4-phenyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-amino-4-cyclopropyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (4-benzylaminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (3-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,

6- (5-aminoadamantan-2-yloxy) -7-methyl-2H-isoquinolin-1-one,

6 - {[(7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,

6 - {[(7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,

3,3-dioxide 6 - {[(7-amino-3- (dioxothia) bicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one or

6- (1-azaspiro [4.5] dec-8-yloxy) -7-chloro-2H-isoquinolin-1-one,

their stereoisomeric and / or tautomeric forms and / or their pharmaceutically acceptable salts.

In a further embodiment, the compounds of formula (I) are selected from the group consisting of

cis-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,

trans-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,

6 - {[(7-endo, 9-anti) -7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,

6 - {[(7-endo, 9-syn) -7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,

6 - {[(7-endo, 9-anti) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,

6 - {[(7-endo, 9-syn) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one and

3,3-dioxide 6 - {[(7-endo, 9-anti) -7-amino-3- (dioxothia) bicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H )-she,

their stereoisomeric and / or tautomeric forms and / or their pharmaceutically acceptable salts.

In any embodiments of the present invention, one or more, or all of the groups contained in the compounds of formula (I), may independently, meet any of the preferred, more preferred or most preferred definitions of the groups indicated above; or correspond to any or some of the specific meanings of the groups that are encompassed by the definitions of groups and specified above, to all combinations of preferred, more preferred or most preferred definitions of groups and / or specific meaningful definitions of groups that are the subject of the present invention. With respect to all preferred embodiments of the invention, the invention also includes compounds of formula (I) in all stereoisomeric forms, mixtures of stereoisomeric forms in all ratios, as well as pharmaceutically acceptable salts thereof.

A substituted isoquinoline sample is numbered according to IUPAC rules:

The terms "isoquinolone and isoquinolinone" are used synonymously.

All references to “compound (s) of formula (I)” herein refer to compound (s) of formula (I), (II) (IIIa), (IIIb) and (IV) described above and their pharmaceutically acceptable salts and / or their stereoisomeric forms, polymorphs and solvates. The physiologically functional derivatives described herein are also included.

Pharmaceutically acceptable salts of the compounds of formula (I) mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17 ^th edition, page 1418 (1985)). For acid groups, preference is given, among others, to the salts of sodium, potassium, calcium and ammonium, due to their physical and chemical stability and solubility. For the main groups, preference is given, among others, to the salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methyl sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid; or salts of carboxylic acids or sulfonic acids, such as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates and salts of amino acids, natural bases or carboxylic acids. The preparation of pharmaceutically acceptable salts from the compounds of formula (I), which are capable of forming salts, including their stereoisomeric forms, takes place essentially by a known method. The compounds of formula (I) form stable alkali metal, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or other basic amino acids, for example lysine, ornithine or arginine. In the case where the compounds of formula (I) have basic groups, then stable acid addition salts can also be obtained with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic acid and tartaric acid. A preferred salt is the hydrochloride salt.

Salts with a pharmaceutically unacceptable anion, such as, for example, trifluoroacetate, are likewise within the scope of the invention as intermediates useful in the preparation or purification of pharmaceutically acceptable salts and / or for use in non-medical, for example, in vitro applications.

The present invention also includes derivatives of the compounds of formula (I) that are physiologically functional. The term “physiologically functional derivative” as used herein refers to any physiologically acceptable derivative of a compound of formula (I) according to the invention, for example an N-oxide, which when administered to a mammal, such as, for example, a human, is capable of forming (directly or indirectly) a compound formula (I) or its active metabolite.

Derivatives that are physiologically functional include a prodrug of a compound of the invention as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such a prodrug can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be active themselves.

The invention relates to compounds of formula (I) in the form of their stereoisomeric forms, which include racemates, enantiomerically enriched mixtures, pure enantiomers and diastereomers, and mixtures thereof in any ratio.

The compounds of the invention can also be in various polymorphic forms, for example, in the form of amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and constitute an additional aspect of the invention.

If radicals or substituents can occur several times in the compounds of formula (I), all of them, independently of each other, can have a given value and be identical or different.

The present invention also relates to compounds of formula (I) and / or their pharmaceutically acceptable salts for use as pharmaceutical products (or drugs). It relates to the use of compounds of formula (I) and / or their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment and / or prophylaxis of diseases associated with Rho kinase and / or Rho kinase-mediated phosphorylation of myosin light chain phosphatase, i.e. treatment and / or prevention of hypertension, pulmonary hypertension, eye hypertension, retinopathy and glaucoma, peripheral circulatory disorders, peripheral arterial occlusive disease (PAOD), coronary heart disease, angina pectoris, heart pertrophy, heart failure, ischemic diseases, ischemic organ failure, terminal organ damage, pneumofibrosis, liver fibrosis, liver failure, nephropathy, including nephropathy induced by hypertension, nephropathy not induced by hypertension and diabetic nephropathy, renal fibrosis, renal fibrosis, hypertrophy of organs, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, t ombotic disorders, stroke, cerebrovascular spasm, cerebral ischemia, pain, such as neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, intestinal infections, you bathrooms with bacteria, sepsis, development and progression of cancer, such as breast, colon, prostate, ovaries, brain and lung and their metastases.

In a further embodiment, the invention also relates to the use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof for the treatment and / or prophylaxis of hypertension, pulmonary hypertension, liver fibrosis, liver failure, nephropathy, renal failure, chronic obstructive pulmonary disease (COPD) cerebrovascular spasm, pain, damage to the spinal cord, erectile dysfunction, restenosis of blood vessels or the development and progression of cancer.

The present invention further relates to pharmaceuticals (or pharmaceutical compositions) that contain an effective amount of at least one compound of formula (I) and / or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, that is, one or more pharmaceutically acceptable carrier substances (or fillers) and / or additives (or fillers). Pharmaceutical agents can be administered orally, for example in the form of pills, tablets, glazed tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the introduction can, in addition, be carried out rectally, for example, in the form of suppositories; or parenterally, for example, intravenously, intramuscularly or subcutaneously, in the form of injection solutions or solutions for infusion, microcapsules, implants or plates; or transdermally or topically, for example, in the form of ointments, solutions or tinctures; or in other ways, for example in the form of aerosol or nasal sprays.

The pharmaceutical agents of the invention are prepared in a manner known per se and are familiar to one skilled in the art using pharmaceutically acceptable inert inorganic and / or organic carrier materials and / or additives, in addition to the compound (s) of formula (I) and / or its (their) pharmaceutically acceptable salts and / or its (their) prodrugs. To obtain pills, tablets, coated tablets and hard gelatine capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and so on can be used. Carrier materials for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, and so on. Suitable carrier materials for the preparation of emulsions or syrups or solutions, for example injection solutions, are, for example, water, physiological saline, alcohols, glycerin, polyols, sucrose, invert sugar, glucose, vegetable oils and so on. Suitable carrier materials for microcapsules, implants or plates are, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical agents typically contain from about 0.5 to about 90% by weight of the compounds of formula (I) and / or their pharmaceutically acceptable salts and / or their prodrugs. The amount of the active ingredient of formula (I) and / or its pharmaceutically acceptable salts and / or its prodrugs in pharmaceuticals is usually from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of formula (I) and / or their pharmaceutically acceptable salts and carrier materials, pharmaceuticals may contain one or more additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers , preservatives, sweeteners, colorants, substances that change the taste and smell, flavors, thickeners, diluents, buffering agents, solvents, solubilizers, agents that contribute to the achievement of depot effect one salt changing the osmotic pressure, coating agents and antioxidants. They may also contain two or more compounds of formula (I) and / or their pharmaceutically acceptable salts. In the case where the pharmaceutical agent contains two or more compounds of formula (I), the selection of the individual compounds may aim at a specific general pharmacological profile of the pharmaceutical agent. For example, a potent high potency compound with a shorter duration of action may be combined with a longer potent compound of less potency. Allowed flexibility regarding the choice of substituents in the compounds of formula (I) provides great opportunities for regulating the biological and physico-chemical properties of the compounds, and thus allows the selection of such demanded compounds. Moreover, in addition to at least one compound of formula (I) and / or its pharmaceutically acceptable salts, the pharmaceutical agents may also contain one or more other therapeutically or prophylactically active ingredients.

When using the compounds of formula (I), the dose can be varied within wide limits. As usual and as the doctor knows, it should correspond to the specific conditions of each individual case. It depends, for example, on the particular compound that is used, on the nature and severity of the disease to be treated, on the method and schedule of administration, or on whether an acute or chronic condition is treated or prevented. An appropriate dosage can be established using clinical indications for use, well known in medical practice. Generally speaking, the daily dose required to achieve the desired results in adult patients with a body weight of about 75 kg is from about 0.01 to about 100 mg / kg, preferably from about 0.1 to about 50 mg / kg, in particular from about 0.1 to about 10 mg / kg, (in each case, refer to the amount of mg of the drug per 1 kg of body weight of the patient). In particular, in the case of administration of relatively large quantities, the daily dose may be divided into several, for example, 2, 3 or 4, parts for administration. As usual, depending on the individual condition of the patient, it may be necessary to deviate from the indicated daily dose in the direction of increase or decrease.

Moreover, compounds of formula (I) can be used as synthesis intermediates for the preparation of other compounds, in particular other pharmaceutically active ingredients, which can be obtained from compounds of formula (I), for example, by the introduction of substituents or modification of functional groups.

The compounds of formula (I) can be prepared as follows.

The compounds of general formula (I) may be composed of an appropriately substituted isoquinoline moiety and an appropriately substituted cycloalkylamine moiety.

Isoquinolines and isoquinolones, such as structures (i) or (ii) containing a residue suitable for the combination at 6, can be obtained using a wide variety of methods, for example, those discussed by Alvarez et al. Science of Synthesis 2005, 15, 661-838 and 839-906 and in the references cited therein. In addition, isoquinolines can be converted to isoquinolones by methods described in the literature, for example, in WO 2007/012421 or WO 2007/012422; such as converting a suitable isoquinoline to the corresponding N-oxide with an oxidizing agent such as hydrogen peroxide or metachloroperbenzoic acid; followed by conversion to the corresponding 1-chloro derivative using a chlorinating agent such as phosphorus oxychloride, followed by substitution of chlorine with alcohol under alkaline conditions, such as sodium methylate in methanol or conversion to the corresponding 2H-isoquinolone, for example, treatment with ammonium acetate in acetic acid at high temperature. It is understood that the hydroxyl group at position 6 of compound (ii) can be released at an appropriate synthesis step, for example by treating the corresponding 6-methoxy derivative with lewis acids such as aluminum chloride or boron tribromide. It is all the more clear that 2H-isoquinolones can be converted to suitably protected 1-alkoxyisoquinolones by a variety of methods, for example, by treating the corresponding 2H-isoquinolones with alkylating agents such as benzyl bromide or methyl iodide in the presence of a suitable base such as silver carbonate or triethylamine, in a suitable solvent, such as toluene or THF; or by converting said 2H-isoquinolones into their 1-chloro derivatives by treatment with a chlorinating agent, such as phosphorus oxychloride, followed by substitution of chlorine with alcohol, for example, under basic conditions, such as sodium methylate in methanol. It is understood that the residues R ₃ , R ₄ , R ₅ , R ₇ and / or R ₈ can either be introduced into the starting materials for the synthesis of the corresponding isoquinoline or isoquinolone, or they can be introduced at the corresponding later stage, for example, by halogenation, such such as bromination or chlorination, and subsequent substitution of said halogen by methods well represented in the literature, such as, for example, Suzuki or Hartwig Buchwald combinations using the appropriate catalysts and such reagents involved in the combinations as boronic acids, amines or anilines us.

As an illustration, one possible synthesis of isoquinolinone (v) substituted with cycloalkylamine, which, however, does not limit the present invention, is described below. Cycloalkylamine-substituted isoquinolinones (e.g., compound v) can be synthesized in a variety of ways. The following General Scheme 1 illustrates some of the possible ways to obtain isoquinolinones, but does not limit the present invention.

6-fluoroisoquinolones (i), for example, substituted by R ₃ , R ₄ , R ₅ , R ₇ and / or R ₈ groups, which, for example, being independent of each other with substituents, such as hydrogen, alkyl, alkoxy or halide, may be reacted with suitable R ₁₁ / R ₁₂ substituted amino alcohols, where R ₁₁ / R ₁₂ independently represent, for example, hydrogen, alkyl or a protective group, such as, for example, Boc (tert-butyloxycarbonyl) or Cbz (benzyloxycarbonyl ), in the presence of a base such as DBU, cesium carbonate or sodium hydride, at temperatures at odyaschihsya in the range between ambient temperature and 100 ° C, to give the corresponding derivatives (iv). This conversion, optionally, can be performed already at earlier stages of the synthesis (for example, by reaction of the corresponding intermediate compound). It is understood that in the case of unprotected isoquinolones, this may require the protection of the nitrogen or oxygen atoms of the isoquinolone moiety using suitable methods, such as reacting with suitably substituted alkyl or benzyl halides in the presence of a base.

Alternatively, amino alcohols can be attached to 6-hydroxyisoquinolones, such as (ii), by inverting the hydroxyl-containing carbon center of compounds such as (iii) either protected by the corresponding protecting group Q or unprotected by the Mitsunobu reaction using triphenylphosphine and dialkyl azodicarboxylates, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, in a suitable solvent, such as tetrahydrofuran, or toluene.

Then, products such as a compound of type (iv) obtained by these methods can be or isolated to give compounds of type (v); or, in the presence of an appropriate amino group, reacted with the corresponding aldehydes or ketones in the presence of a reducing agent, such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, in a suitable solvent and in the presence of a water-removing agent such as molecular sieves or a suitable ortho-ester. This amino group may need to be removed at the initial stage, similarly, for example, to the acid removal of Boc groups. Moreover, the amino group can be acylated through its reaction with a suitable acid chloride in the presence of a base such as triethylamine or Hunig base; or by reacting it with a suitable carboxylic acid in the presence of a base such as triethylamine or a Hunig base and a coupling reagent such as EDC, PyBOP or TOTU.

In the case of using protected isoquinolones, cleavage of the used protecting groups is necessary to isolate the desired isoquinolone (v). This isolation, however, can be carried out before or after the reductive amination step, depending on the nature of the aldehyde / ketone used and the protecting group used.

Derivatives of isoquinolone, such as compound (v), can be obtained in the form of free bases or in the form of various salts, such as, for example, hydrochlorides, hydrobromides, phosphates, trifluoroacetates, sulfates or fumarates. The resulting salts can be converted to the corresponding free base, either by ion exchange chromatography or, for example, by treatment with aqueous alkali followed by extraction with suitable organic solvents, such as, for example, tert-butyl methyl ether, chloroform, ethyl acetate or isopropanol / dichloromethane mixtures, followed by evaporation to dryness.

Cycloalkylamine moieties, such as, for example, (iii) can be synthesized in a variety of ways. The following general schemes illustrate some of the possible ways to obtain amines, without limiting, however, the present invention. It is within the competence of a person skilled in the art to replace the exemplary compounds shown in the diagrams and the exemplary reagent shown in the text with appropriate alternative compounds or reagents, or, if appropriate, omit or add some synthesis steps.

The synthesis of cycloalkylamino alcohol (iii) is approximately described in Scheme 2, but without limiting the range of substituents of the present invention.

The cycloalkylamine portion (iii) can, for example, be obtained from the corresponding diketone, which is subjected to monoketalization to obtain compound (vi) by treatment with an appropriate diol, such as ethylene glycol, in the presence of an acid such as p-toluenesulfonic acid. It is understood that compound (vi) can, for example, also be obtained by mono-removing the protection of the corresponding diketal or by oxidizing the corresponding alcohol precursor to the corresponding ketone by reaction with an appropriate oxidizing agent, such as, for example, manganese or reagents containing chromium, or reagents containing hypervalent iodine. Then, compound (iv) can be converted, for example, to an amine of type (vii) by reaction with an amine such as ammonia, benzylamine or ethylamine, in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, possibly in the presence of a Lewis acid. Ketone (viii) can be obtained, for example, by treating compound (vii) under acidic conditions, such as acetone and hydrochloric acid, or aqueous acetic acid, at elevated temperature. The ketone can then be converted to alcohol (iii) by reaction with appropriate reducing agents, such as sodium borohydride, in an appropriate solvent, such as methanol, ethanol or THF (THF).

For example, the hydroxy group of compound (iii) can be converted to a thiol by the Mitsunobu reaction using thioacetate followed by alkaline cleavage with a suitable alkali, which leads to amine moieties of type (x). Then, these thiols, after combination with the corresponding isoquinolinones under the applicable reaction conditions, for example, conditions similar to those shown above in Scheme 1, describing the combination of compound (iii)) can be used to obtain the compound of formula (I) with the linker unit L = S; or optionally can be oxidized, using methods known to those skilled in the art, to the corresponding sulfoxides and sulfones (to obtain compounds of formula (I) with a linker unit L = SO and SO ₂ ). The corresponding amines can be obtained through a reductive amination step, starting from ketones, such as compound (viii), using suitable amines in the presence of a reducing agent such as sodium triacetoxy borohydride, sodium borohydride or sodium cyanoborohydride, in the presence of a water removing agent such as molecular sieves or a suitable ortho -ether.

One option for introducing R ₉ residues at the α-position to the amine is by reacting a suitably protected ketone, such as compound (vi), with a source of amines, such as ammonia, and a suitable organometallic reagent, such as allyl borane, in a suitable solvent. Another option is the interaction of the protected alcohols (xii) with a reagent such as 2-methyl-2-propanesulfinamide to the corresponding sulfimine (xiii), which can then be reacted with a suitable organometallic reagent such as aryl lithium or Grignard reagents to obtain amines of type (xiv), which can then be converted further.

Another option is the construction of derivatives of bicyclic or polycyclic carbocyclic acids containing ketoparticles or protected ketoparticles, such as compound (xv), by carrying out a Curtius reaction; for example, initially converting the acid to acyl azide by treatment with a chlorinating agent such as sulfonyl chloride or thionyl chloride, and then reacting with a source of azides, such as sodium azide, in a suitable solvent, followed by reacting said acid chloride at elevated temperature to give the corresponding isocyanate that can be trapped using a suitable alcohol, such as benzyl alcohol, to obtain the corresponding carbamate protected amine. Then the connection (xvi) can be further converted.

Generally speaking, protecting groups that may still be present in products obtained by coupling reactions are then removed by standard procedures. For example, tert-butyl protecting groups, in particular a tert-butoxycarbonyl group, which is a form of protecting an amino group, can be removed, i.e. converted to an amino group, by treatment with trifluoroacetic acid. As already explained, after the coupling reaction, functional groups can also be generated from suitable precursor groups. In addition, the conversion to a pharmaceutically acceptable salt or prodrug of a compound of formula (I) can then be carried out by known methods.

Generally speaking, a reaction mixture containing a final compound of formula (I) or an intermediate is treated and then, if desired, the product is purified by conventional methods known to those skilled in the art. For example, a synthesized compound can be purified using well-known methods, such as crystallization, chromatography or high-performance liquid chromatography with reverse phase (RP-HPLC) (RP-HPLC), or other separation methods based, for example, on size, charge or hydrophobicity connections. Similarly, well-known methods, such as NMR, IR and mass spectrometry (MS) (MS), can be used to characterize the compounds of the invention.

EXAMPLES

The following examples illustrate various embodiments of the present invention and form part of the present invention.

1-benzyloxy-7-chloro-6-fluoroisoquinoline (1)

7-chloro-6-fluoro-2H-isoquinolin-1-one (obtained according to WO 2007/012422, 52.2 g) was dissolved in THF (THF) (1 L). After adding silver carbonate (145.5 g) and benzyl bromide (40.6 ml), the mixture was stirred at room temperature overnight. An additional 6.2 ml of benzyl bromide was added and the mixture was stirred at 70 ° C for 2 hours. After cooling to room temperature, the reaction mixture was diluted by adding 1 L of ethyl acetate, and filtered over celite. The filter cake was washed thoroughly, the organic layer was evaporated and chromatographed on silica gel (n-heptanes: methyl tert-butyl ether) to give 27.8 g of the title compound. R _t (retention time) = 3.73 min (method 1). Defined mass: 288.1 (M + H ⁺ ).

1-benzyloxy-6-fluoro-7-methylisoquinoline (2)

6-fluoro-7-methyl-2H-isoquinolin-1-one (prepared as described in WO2007012421, 13.2 g, mmol) was dissolved in tetrahydrofuran (175 ml). After the addition of silver carbonate (41.2 g), benzyl bromide (15.3 g) was added dropwise. The mixture was stirred overnight. The mixture was heated to 70 ° C and another 3 ml of benzyl bromide was added. Heating was continued until they ceased to observe a further transformation. The mixture was taken up in ethyl acetate, filtered over celite, evaporated and the residue was taken up in a small amount of ethyl acetate. The precipitate formed was filtered to obtain 3.0 g of compound (2). The mother liquor was concentrated and chromatographed on silica gel to give an additional 8.6 g of compound (2). R _t = 4.00 min (method 2). Defined mass: 268.1 (M + H ⁺ ).

4-allyl-4-aminoadamantan-1-ol (3)

5-hydroxy-2-adamantanone (3.0 g, 18.1 mmol) was dissolved in a solution of ammonia in methanol (7N, 26 ml, 180 mmol, 10 equiv.) And stirred for 15 min at room temperature. Then, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (5.4 ml, 28.9 mmol, 1.6 eq.) Was added dropwise. The reaction mixture was stirred for 16 hours at room temperature before removing the volatiles in vacuo. The residue was taken up twice with methanol and evaporated, then lyophilized from water to give 4-allyl-4-aminoadamantan-1-ol (3) as a mixture of diastereomers. R _t = 1.05 min, 1.79 min (method 2). Defined mass: 270.3 (M + H ⁺ ).

4-propyl-4-aminoadamantan-1-ol (4)

A solution of 4-allyl-4-aminoadamantan-1-ol (3.6 g, 17.4 mmol) in methanol (50 ml) was treated with 50 mg of 10% palladium on activated carbon, the mixture was stirred overnight in a hydrogen atmosphere ( 1 atm.) At room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to obtain 2.8 g of the title compound as a diastereomeric mixture (4). R _t = 0.21 min, 0.73 min (method 3). Defined mass: 210.2 (M + H ⁺ ).

[5- (tert-butyldimethylsilanyloxy) adamantane- (2E) -ilidene] 2-methylpropane-2-sulfinic acid amide (5)

To a solution of 5- (tert-butyldimethylsilanyloxy) adamantan-2-one (1.00 g, 3.57 mmol) in tetrahydrofuran (2.5 ml) was added titanium (IV) ethylate (1.12 ml, 5.35 mmol, 1.5 equiv.) And 2-methyl-2-propanesulfinamide (454 mg, 3.74 mmol, 1.05 equiv.). The resulting mixture was stirred for 6 hours at the boil under reflux and 16 hours at room temperature, before pouring with rapid stirring into an equal volume of a saturated aqueous solution of NaHCO ₃ and filtered through celite. The filter cake was washed with ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to afford 1.00 g of the title compound. R _t = 2.25 min (method 3). Defined mass: 384.3 (M + H ⁺ ).

[5- (tert-butyldimethylsilanyloxy) -2-phenyladamantan-2-yl] 2-methylpropan-2-sulfinic acid amide (6)

A solution of [5- (tert-butyldimethylsilanyloxy) adamantane- (2E) -ilidene] 2-methylpropane-2-sulfinic acid amide (5, 1.50 g, 3.91 mmol) in diethyl ether (10 ml) was added dropwise to 0.5 M solution of phenylmagnesium chloride in diethyl ether (17.2 ml, 8.60 mmol, 2.2 eq.), Pre-cooled to -78ºC. The reaction solution was allowed to warm to room temperature overnight. An equivalent of phenylmagnesium chloride (1.8 M in diethyl ether, 2.2 ml) was added and the reaction mixture was further stirred for 2 hours. The reaction mixture was cooled to 0 ° C, quenched by adding dropwise a saturated aqueous solution of Na ₂ SO ₄ , dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1.41 g of the title compound (6) as a diastereomeric mixture. R _t = 5.19 min (method 4). Defined mass: 462.2 (M + H ⁺ ).

4-phenyl-4-aminoadamantan-1-ol (7)

To a solution of [5- (tert-butyldimethylsilanyloxy) -2-phenyladamantan-2-yl] amide 2-methylpropan-2-sulfinic acid (6) in 2-propanol (10 ml) was added 1 N hydrochloric acid (5 ml) and the mixture was stirred at room temperature until complete conversion was achieved. The reaction mixture was washed with diethyl ether. The aqueous phase was concentrated in vacuo and lyophilized to obtain 676 mg of the diastereomeric mixture of 4-phenyl-4-aminoadamantan-1-ol (7) in the form of its hydrochloride. R _t = 0.33 min, 0.85 min (method 3). Defined mass: 227.2 (M-NH ₃ + H ⁺ ).

The following products were synthesized as a mixture of diastereomers in the form of their hydrochlorides, as described in the synthesis of compound 7, starting from [5- (tert-butyldimethylsilanyloxy) adamantane- (2E) -ilidene] 2-methylpropane-2-sulfinic acid amide (5 ) and the corresponding Grignard reagents.

Compound No. Product Chemical name [M + H ⁺ ] R _t / [min] Way 8

4-methyl-4-aminoadamantan-1-ol 182 0.18, 0.52 3 9

4-cyclopropyl-4-aminoadamantan-1-ol 191 [M-NH ₃ + H ⁺ ] 0.19, 0.66 3

Synthesis of 5-aminoadamantan-2-ol (14)

a) 4-Oxoadamantane-1-carboxylic acid methyl ester (10)

38 ml of fuming sulfuric acid was placed in a two-necked flask and heated to 60 ° C. Over 2 hours, 1.5 g of 5-hydroxy-2-adamantanone dissolved in formic acid (8.5 ml) was added dropwise. Another 9 ml of formic acid was added over 2 hours, and stirring was continued for 1 hour at 60 ° C. and at room temperature overnight. Under ice cooling, the reaction mixture was poured onto 100 ml of dry methanol, stirred for 2 hours at room temperature and then poured onto 400 ml of ice. The aqueous layer was extracted three times with dichloromethane. The combined organic layer was dried over sodium sulfate and evaporated to dryness to give 1.64 g of the desired product. R _t = 1.75 min (5). Defined mass: 209.2 (M + H ⁺ ).

b) 4-oxoadamantane-1-carboxylic acid (11)

1.64 g of 4-oxo-adamantane-1-carboxylic acid methyl ester (10) was dissolved in 4 ml of a 2 M aqueous LiOH / MeOH mixture (1: 1) and stirred overnight at room temperature. An additional 5 ml of a mixture of MeOH / LiOH was added and stirring was continued until complete conversion. The reaction mixture was acidified and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness to give 1.4 g of compound (11) as a solid. R _t = 0.87 min (method 3). Defined mass: 195.2 (M + H ⁺ ).

c) (4-Oxoadamantan-1-yl) carbamic acid benzyl ester (12)

Together with toluene, 0.7 g of 4-oxo-adamantane-1-carboxylic acid (11) was twice distilled and dissolved in 5.5 ml of dry toluene. 1.1 ml of triethylamine was added. At 0 ° C, 0.9 ml of diphenylphosphoryl azide was added dropwise. The mixture was allowed to warm to room temperature, and then the mixture was placed in a preheated cuvette at 90 ° C. The mixture was heated until gas evolution ceased (approximately 1.5 hours). 1.9 ml of benzyl alcohol was added and stirring was continued at 100 ° C. When the reaction was completed, the reaction mixture was cooled to room temperature, then ethyl acetate was added and the mixture was extracted twice with a 1 M aqueous solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate and evaporated. The resulting oil was subjected to silica gel chromatography (heptanes: ethyl acetate) to obtain 871 mg of the desired product. R _{t =} 1.40 min (method 3). Defined mass: 300.2 (M + H ⁺ ).

d) (4-Hydroxyadamantan-1-yl) -carbamic acid benzyl ester (13)

865 mg of (4-oxoadamantan-1-yl) carbamic acid benzyl ester (12) was dissolved in 15 ml of THF and 109 mg of sodium borohydride was added at 0 ° C. Stirring was continued for 2 hours, then the reaction mixture was acidified by adding a 2 M HCl solution. The reaction mixture was extracted three times with ethyl acetate, and the combined organic layer was dried over sodium sulfate and evaporated. The resulting oil was separated by HPLC to obtain 463 mg of the desired product as a cis / trans mixture together with 119 mg of the cis derivative (13a) and 10 mg of the trans derivative (13b). 13a: R _t = 1.37 min (method 3). Defined mass: 302.3 (M + H ⁺ ). 13b: R _t = 1.39 min (method 3). Defined mass: 302.3 (M + H ⁺ ).

e) 5-aminoadamantan-2-ol (14)

113 mg of product (13a) was dissolved in 13.5 ml of methanol and 15 mg of 10% Pd on activated carbon was added. Stirring in a hydrogen atmosphere was continued for 3 hours until the reaction was complete. The catalyst was filtered off and the resulting organic layer was evaporated to obtain 63 mg of the desired product. R _t = 0.36 min (method 3). Defined mass: 168.2 (M + H ⁺ ).

In a similar manner, it was possible to remove the protection of compound (13b) and in the cis / trans mixture (13) to obtain the corresponding amino alcohols (14b and 14) used for the combination.

Synthesis of 6- (4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one (Example 1 and Example 2)

a) 5- (1-benzyloxy) -7-chloroisoquinolin-6-yloxy) adamantan-2-ylamine (15)

To a suspension of sodium hydride (60% in mineral oil, 417 mg, 10.4 mmol, 3 equiv.) In dimethylacetamide (7 ml) was added a solution of 4-aminoadamantan-1-ol (640 mg, 3.82 mmol, 1.1 equiv.) in dimethylacetamide (7 ml). After stirring for 60 min at room temperature, a solution of 1-benzyloxy-7-chloro-6-fluoroisoquinoline (1, 1.0 g, 3.48 mmol) in dimethylacetamide (7 ml) was added and stirring was continued at room temperature until completion reactions. The reaction was quenched by adding water (15 ml) and the reaction mixture was extracted twice with a mixture of dichloromethane and 2-propanol (3: 1). The combined organic layers were evaporated, water was added and the mixture was lyophilized to remove dimethylacetamide residues. The resulting crude product was purified by flash chromatography (SiO ₂ , 0% → 30% methanol in dichloromethane) to give 473 mg of the title compound as a diastereomeric mixture. R _t = 1.35 min, 1.55 min (method 3). Defined mass: 435.2 (M + H ⁺ ).

b) 6- (4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one (example 1 and example 2)

A solution of 5- (1-benzyloxy) -7-chloroisoquinolin-6-yloxy) adamantan-2-ylamine (15, 473 mg) in 2-propanol (4 ml) was treated with 1 N aqueous hydrochloric acid (2 ml) and stirred at room temperature until complete conversion was observed. The reaction mixture was evaporated and lyophilized twice from water to obtain 385 mg of a crude product. Purification by preparative HPLC and lyophilization of 1 N. HCl and water gave 10 mg of the pure diastereoisomer of sample 1 and 11 mg of sample 2 in the form of their respective hydrochlorides, together with an additional substance in the form of a mixture of isomers. Example 1: R _t = 2.40 min (method 4). Defined mass: 345.1 (M + H ⁺ ). Example 2: 2.38 min (method 2). Defined mass: 345.1 (M + H ⁺ ). Relative stereochemistry was not established.

The following samples were synthesized as hydrochlorides from the corresponding aminoadamantanols and 1-benzyloxy-7-chloro-6-fluoroisoquinoline (1) using a procedure similar to that described for example in Example 1. Aminoadamantanols were either commercial substances (Example 13) , the synthesis of which is described above (examples 3-11, 14 and 15), or the synthesized substances described above. In the case of Example 16, 1-benzyloxy-7-methyl-6-fluoroisoquinoline (2) was used as an isoquinoline structural unit.

If the diastereoisomers could not be separated at an earlier stage of the synthesis, products with remote protection were purified by preparative HPLC and lyophilized from 1 N HCl and water, respectively. In the case of Example 14 and Example 15 (synthesized from a cis / trans mixture (13), it was possible to separate the cis / trans isomers after the coupling carried out in step a) by chromatography on silica gel (dichloromethane / methanol mixture) as O- benzyl protected isoquinolinones.

For examples 3-10, relative stereochemistry was not established.

Example No. Product Isomer Chemical name [M + H ⁺ ] R _t / [min] Way 3

one 6- (4-allyl-4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 385.2 1.10 one four

2 6- (4-allyl-4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 385.2, 368.1 [M-NH ₃ + H ⁺ ] 2.05 2 5

one 6- (4-amino-4-propyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 370.1 [M-NH ₃ + H ⁺ ] 2.59 four 6

2 6- (4-amino-4-propyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 370.2 [M-NH ₃ + H ⁺ ] 2.41 2 7

one 6- (4-amino-4-methyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 359.2, 342.1 [M-NH ₃ + H ⁺ ] 2.17 2

8

2 6- (4-amino-4-methyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 342.1 [M-NH ₃ + H ⁺ ] 2.23 2 9

one 6- (4-amino-4-phenyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 404.2 [M-NH ₃ + H ⁺ ] 2.41 2 10

2 6- (4-amino-4-phenyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 421.2, 404.2 [M-NH ₃ + H ⁺ ] 2.59 2 eleven

1 + 2 6- (4-amino-4-cyclopropyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 368.2 [M-NH ₃ + H ⁺ ] 0.94, 0.99 3 12

1 + 2 6- (4-benzylaminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 435.2 2.45, 2.53 2

13

6- (3-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one 345.1 0.93 3 fourteen

one cis-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one 345.2 1.87 2 fifteen

2 trans-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one 345.2 1.92 2

16

1 + 2 6- (5-aminoadamantan-2-yloxy) -7-methyl-2H-isoquinolin-1-one 325,2 1.87 2

(9-Oxo-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid benzyl ester (16)

a) A mixture of triethylamine (10.1 ml, 72 mmol) and 3,6-dihydro-4- (1-pyrrolidinyl) -2H-thiopyran (12.9 g, 76 mmol, prepared according to the procedure described in Tetrahedron Asymmetry 1997, 1811-1820) in anhydrous acetonitrile (55 ml) was heated to reflux, then ethyl 3-bromo-2- (bromomethyl) propionate (14.6 g, 53 mmol) in dry acetonitrile was added dropwise over 45 minutes ml). The resulting reaction mixture was refluxed for another 1.5 hours, then cooled to room temperature before adding a 10% aqueous solution of acetic acid (5.2 ml). Then the mixture was refluxed for 1 hour and evaporated to dryness. Saturated brine was added to the residue, the aqueous phase was extracted with ethyl acetate, the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 9-oxo-3-thiabicyclo [3.3.1] nonane-7-carboxylic acid ethyl ester in as a brown oil (15.5 g).

b) To a solution of 9-oxo-3-thiabicyclo [3.3.1] nonane-7-carboxylic acid ethyl ester (5 g, 22 mmol) in a mixture of THF (55 ml) / water (30 ml) at 0 ° C dropwise 1 n was added. sodium hydroxide solution (24 ml, 24 mmol). The reaction mixture was stirred at room temperature overnight, then heated to 60 ° C for 1 hour before evaporation of THF. The remaining aqueous layer was washed with ethyl acetate, acidified with 1 N. HCl; the resulting precipitate was filtered and dried to obtain 9-oxo-3-thiabicyclo [3.3.1] nonane-7-carboxylic acid (2.22 g) as a solid.

c) A mixture of 9-oxo-3-thiabicyclo [3.3.1] nonane-7-carboxylic acid (2.22 g, 11 mmol), triethylamine (1.7 ml, 12 mmol) and diphenylphosphorylazide (2.6 ml, 12 mmol) in dry toluene (20 ml) was stirred for 2 hours at room temperature, then was refluxed for another 2 hours and cooled to room temperature. Benzyl alcohol (11.4 ml, 110 mmol) was added, the solution was refluxed overnight and evaporated to dryness. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (cyclohexane: ethyl acetate 1: 1) to obtain crude (9-oxo-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid benzyl ester (16, 4.5 g). R _t = 4.6 min (method 6), Specific mass: 306.1 (M + H ⁺ ).

(7-endo) -7-amino-3-oxabicyclo [3.3.1] nonan-9-ol (17)

a) To a solution of benzyl ether (9-oxo-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid (16, 4.2 g, 13.7 mmol) in ethanol (172 ml), sodium borohydride ( 0.78 g, 20.6 mmol) at room temperature. The solution was stirred for 1 hour before the addition of sodium borohydride (0.2 g, 5 mmol). The reaction mixture was stirred for 2 days, an additional portion of sodium borohydride (0.340 g, 9 mmol) was added, and stirring was continued for 4 hours. The mixture was then concentrated under reduced pressure, and cold water and dichloromethane were added to the residue. After extracting the aqueous phase with dichloromethane, the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (cyclohexane: ethyl acetate 40:60) to obtain 9-hydroxy-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid benzyl ester as a white solid (0.84 g) .

b) A solution of benzyl ether (9-hydroxy-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid (0.19 g, 0.63 mmol) in 6N HCl (0.3 ml, 1.8 mmol) was refluxed for 1 hour. Then the reaction mixture was cooled to room temperature and evaporated together with toluene to give the title compound in the form of its hydrochloride as a colorless oil (110 mg). Defined mass: 173 (m / z, EI (electronic ionization)).

3,3-dioxide (7-endo) -7-amino-3-oxabicyclo [3.3.1] nonan-9-ol (18)

To a solution of 9-hydroxy-3-thiabicyclo [3.3.1] non-7-yl) carbamic acid benzyl ester (17, step a, 1.5 g, 4.47 mmol) in anhydrous chloroform (28 ml) was added 3- chloroperbenzoic acid (1.54 g, 8.9 mmol). The resulting mixture was stirred at room temperature overnight, then was refluxed for 3 hours before adding another portion of 3-chloroperbenzoic acid (0.75 g, 4.3 mmol). The reaction mixture was refluxed for another 3 hours, then poured onto water and extracted with chloroform. The organic layer was washed with sodium sulfite solution and water before drying over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was used in the next step without any further purification. To 1.15 g of the obtained material in anhydrous methanol (170 ml) was added palladium hydroxide (20% on activated carbon, 0.093 g). The reaction mixture was vigorously stirred under a hydrogen atmosphere (1 bar) for 4 hours before being filtered. Palladium hydroxide (0.47 g) was added to the filtrate, and the resulting suspension was stirred for one hour in a hydrogen atmosphere (3 bar) before being filtered. The filtrate was concentrated in vacuo to give 0.58 g of the title compound (18) as an adhesive, which was used in the next step without any further purification. R _t = 0.40 min (method 7). Defined mass: 206 (M + H ⁺ ).

(7-endo) -7-amino-3-oxabicyclo [3.3.1] nonan-9-ol (19)

Starting from 1- (3,6-dihydro-2H-pyran-4-yl) pyrrolidine (prepared according to the procedure published in Tetrahedron Asymmetry 1997, 1811-1820), the title compound was prepared following the same reaction sequence as described for the synthesis of (7-endo) -7-amino-3-oxabicyclo [3.3.1] nonan-9-ol (17). Defined mass: 157 (m / z, EI).

The following samples were synthesized in the form of hydrochlorides from the corresponding aminoadamantanols and 1-benzyloxy-7-chloro-6-fluoroisoquinoline (1) using the procedures similar to those described in Example 1. After the coupling carried out in step a), the cis / trans isomers were separated by chromatography on silica gel (dichloromethane / methanol) in the form of O-benzyl protected isoquinolinones.

Example No. Product Chemical name [M + H ⁺ ] R _t / [min] Way 17

6 - {[(7-endo, 9-anti) -7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one 335 3.90 8 eighteen

6 - {[(7-endo, 9-syn) -7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one 335 4.04 8 19

6 - {[(7-endo, 9-anti) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one 351 2.82 8 twenty

6 - {[(7-endo, 9-syn) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one 351 2.94 8 21

3,3-dioxide 6 - {[(7-endo, 9-anti) -7-amino-3- (dioxothia) bicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H )-she 383.1 0.50 9

Trans-1-azaspiro [4.5] decan-8-ol (20)

A solution of 669 mg (1.62 mmol) of 9-benzyl-11-iodo-1,4-dioxa-9-azadispiro [4.2.4.2] tetradecane (prepared from 1,4-dioxaspiro [4.5] decan-8-one according to a procedure published in J. Bonjoch et al., Tetrahedron Lett. 2003, 44, 8387) in methanol (30 ml) was treated with 50 mg of 20% palladium hydroxide on an activated carbon carrier, and the mixture was stirred overnight at room temperature in hydrogen atmosphere (1 atm.). The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give crude 9-benzyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradecane, which was immediately dissolved in a 1: 1 mixture of acetone and 6 N aqueous hydrochloric acid (10 ml), and stirred at room temperature. After completion of the reaction, the mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organics were washed with brine and water, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (SiO ₂ , 0% → 100% ethyl acetate in heptane) gave 180 mg (0.74 mmol) of 1-benzyl-1-azaspiro [4.5] decan-8-one, which was dissolved in ethanol (10 ml) and cooled to 0ºC. Sodium borohydride (14 mg, 0.37 mmol, 0.5 eq.) Was then added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours before concentration and partitioning between dichloromethane and saturated aqueous sodium bicarbonate. The mixture was vigorously stirred for 15 minutes before phase separation. The aqueous phase was extracted three times with dichloromethane and twice with a mixture of dichloromethane and 2-propanol (3: 1). The combined organic phases were concentrated in vacuo to give crude trans-1-benzyl-1-azaspiro [4.5] decan-8-ol. The alcohol was dissolved in ethanol (4 ml) containing acetic acid (15 μl), and 15 mg of palladium on activated carbon (10%) was treated. The mixture was stirred in an atmosphere of hydrogen (1 atm.) Until complete conversion. The catalyst was filtered off and the reaction mixture was evaporated to dryness, then subsequently lyophilized from 1N. HCl and water to obtain the crude compound indicated in the title, in the form of its hydrochloride. R _t = 0.17 min (method 3). Defined mass: 156.2 (M + H ⁺ ).

6- (1-azaspiro [4.5] dec-8-yloxy) -7-chloro-2H-isoquinolin-1-one (Example 22)

6- (1-azaspiro [4.5] dec-8-yloxy) -7-chloro-2H-isoquinolin-1-one (Example 22) was synthesized in the form of its hydrochloride from trans-1-azaspiro [4.5] decan-8-ol (20) and 1-benzyloxy-7-chloro-6-fluoroisoquinoline (1) using the procedure described in Example 1. R _t = 2.01 min (method 2). Defined mass: 333.1 (M + H ⁺ ). Ways

Method 1: Stationary phase: Col YMC Jsphere 33 × 2

Gradient: ACN (acetonitrile) + 0.05% TFA (trifluoroacetic acid): H ₂ O + 0.05% TFA
from 5:95 (0 min) to 95: 5 (2.5 min), to 95: 5 (3.0 min) Fluid flow rate: 1 ml / min Method 2: Stationary phase: Waters XBridge C18 Gradient: ACN + 0.05% TFA: H ₂ O + 0.05% TFA
from 5:95 (0 min) to 5:95 (0.3 min), to 95: 5 (3.5 min), to 95: 5 (4 min) Fluid flow rate: 1.3 ml / min Method 3: Stationary phase: Col YMC Jsphere ODS H80 20 × 2 Gradient: ACN: H ₂ O + 0.05% TFA
from 4:96 (0 min) to 95: 5 (2.0 min), to 95: 5 (2.4 min) Fluid flow rate: 1 ml / min Method 4: Stationary phase: Col YMC Jsphere 33 × 2.1 Gradient: ACN + 0.05% TFA: H ₂ O + 0.05% TFA
from 2:98 (0 min) to 2:98 (1 min), to 95: 5 (5 min), to 95: 5 (6.25 min) Fluid flow rate: 1 ml / min

Method 5: Stationary phase: Col YMC Pack Pro C18 RS 33 × 2.1 Gradient: H ₂ O + 0.1% FA (fatty acid): ACN + 0.1% FA
from 95: 5 (0 min) to 5:95 (2.5 min), to 5:95 (3 min) Fluid flow rate: 1 ml / min Method 6: Stationary phase: Gemini C18 speaker, 30 × 4.6 mm Gradient: H ₂ O + 0.1% FA: ACN + 0.1% FA
from 95: 5 (0 min) to 95: 5 (1 min), to 0: 100 (9 min), to 0: 100 (12 min) Fluid flow rate: 1 ml / min Method 7: Stationary phase: Kromasil C18 column, 50 × 2.1 mm, 3.5 μm Gradient: H ₂ O + NH ₄ OAc (5 mM) + 3% ACN: ACN
from 100: 0 (0 min) to 0: 100 (5.5 min), to 0: 100 (7 min) Fluid flow rate: 0.8 ml / min Method 8: Stationary phase: Gemini Column C18.30 × 4.6 mm, 3 μm

Gradient: H ₂ O + 0.1% FA: ACN + 0.1% FA
from 95: 5 (0 min) to 0: 100 (5.5 min), to 0: 100 (7.5 min) Fluid flow rate: 1 ml / min Method 9: Stationary phase: AcquityBEH C18 column, 50 × 2.1 mm, 1.7 μm Gradient: H ₂ O + 0.05% TFA: ACN + 0.035% TFA
from 98: 2 (0 min) to 0: 100 (1.6 min), to 0: 100 (2.1 min), to 98: 2 (3 min) Fluid flow rate: 1 ml / min

Determination of the level of inhibition of Rho kinase

To assess the level of inhibition of Rho kinase, IC ₅₀ values were determined according to the following protocol:

The active human ROCK II recombinant (residues 11-552 of His ₆ -labeled N-terminus of the human ROCK-II recombinant) was purchased from Millipore GmbH, Schwalbach, Germany. The peptide substrate, Fluorescein-AKRRRLSSLRA-COOH, was obtained from JPT Peptide Technologies, Berlin, Germany. Adenosine 5'-triphosphate (ATP), bovine serum albumin (BSA), dimethyl sulfoxide (DMSO), 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes), Brij-35, dithiothreitol (DTT) and Pluronic F -68 were purchased from Sigma-Aldrich, Munich, Germany. Tris (trihydroxymethylaminomethane), magnesium chloride, NaOH, 1 M HCl and EDTA (ethylenediaminetetraacetic acid) were purchased from Merck Biosciences, Darmstadt, Germany. A “complete” protease inhibitor was obtained from Roche Diagnostics, Mannheim, Germany.

Test compounds were diluted to appropriate concentrations in buffer 1 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ , 2 mM DTT, 0.02% (w / v) BSA, 0.01% Pluronic F- 68 and 3% DMSO). The ROCK II enzyme was diluted to a concentration of 100 ng / ml in buffer 2 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ , 2 mM DTT and 0.02% (w / v) BSA). The peptide substrate and ATP (ATP) were diluted in buffer 2 to concentrations of 3 μM and 120 μM, respectively. Two μl of a solution of the compound was mixed with 2 μl of a diluted enzyme in a 384-cell small volume microtiter plate (Greiner, Bio-One, Frickenhausen, Germany) and, by adding 2 μl of a solution containing a peptide substrate and ATP, a kinase reaction was initiated. After 60 min incubation at 32 ° C, the reaction was stopped by adding 20 μl of a solution containing 100 mM Hepes-NaOH, pH 7.4, 0.015% (v / v) Brij-35, 45 mM EDTA and 0.227% reagent 1 for coating the chip (Caliper Lifescience Inc, Hopkinton, MA). Then, the phosphorylation of the peptide substrate was determined on a Caliper 3000 model instrument, essentially as described by Pommereau et al (J. Biomol. Screening 2004, 9 (5), 409-416). The separation conditions were as follows: the pressure was 1.3 psi, the maximum voltage was 1562 V, the minimum voltage was 500 V, and the retention time of a certain voltage value was 200 ms. A positive control (buffer 1 instead of compound) and a negative control (buffer 1 instead of compound and buffer 2 instead of ROCK II) were performed simultaneously for each tablet.

The following products / compounds were tested in this assay using the appropriate form (salt or free base), such as those obtained in the examples described above, and the following activity measurement results were obtained.

Example No. pIC ₅₀ one ++++++ 2 ++++++ 3 ++++++ four +++++ 5 ++++++ 6 +++++ 7 ++++++ 8 ++++++ 9 +++++ 10 +++++ eleven ++++++ 12 +++++ 13 +++++ fourteen +++++++ fifteen +++++++ 16 +++++++ 17 ++++++ eighteen ++++++ 19 ++++++ twenty ++++++ 21 +++++ 22 ++++++

The activity shown is expressed as a negative decimal logarithm of the value of IC ₅₀ (pIC ₅₀ ) as follows:

+: pIC ₅₀ ≤3.0 ++: 3.0≤pIC ₅₀ <4.0 +++: 4.0≤pIC ₅₀ <5.0 ++++: 5.0≤pIC ₅₀ <6.0 +++++: 6.0≤pIC ₅₀ <7.0 ++++++: 7.0≤pIC ₅₀ <8.0 +++++++: 8.0≤pIC ₅₀

Claims (22)

1. The compound of formula (I)

Where
R ₁ represents OH;
R ₃ represents H;
R ₄ represents H;
R ₅ represents H;
R ₇ represents halogen or (C ₁ -C ₆ ) alkyl;
R ₈ represents H;
R ₆ represents one (C ₁ -C ₄ ) alkylene attached to a cycloalkyl ring in which (C ₁ -C ₄ ) alkylene forms a second bond with another carbon atom of the cycloalkyl ring to form a bicyclic ring system,
where in a bicyclic ring system one carbon atom is substituted by a group independently selected from O, S or SO ₂ ;
or, if m and s are 2 or m is 3 and s is 1,
R ₆ represents a CH ₂ —CH— (CH ₂ ) ₂ group which, through one CH ₂ group, is attached to a cycloalkyl ring, and two other CH ₂ groups are attached to different carbon atoms of the cycloalkyl ring,
and if m is 3 and s is 3,
R ₆ represents two methylene groups attached to different carbon atoms of the cycloalkyl ring, where methylene groups or the CH ₂ —CH— (CH ₂ ) ₂ group are attached to the carbon atoms of the cycloalkyl ring and form an adamantane system of the formula

where L can be attached to any secondary or tertiary carbon atom,
or R ₆ together with R ₁₁ and the N atom form a (C ₅ ) heterocycloalkyl, which is connected to the cycloalkyl residue in the form of a spirocyclic ring system, where the bicyclic ring system or adamantane system, or containing (C ₅ ) heterocycloalkyl ring system are unsubstituted or optionally substituted with R ₉ ;
R ₉ represents
(C ₁ -C ₆ ) alkyl,
(C ₂ -C ₆ ) alkenyl,
(C ₆ ) aryl
or
cyclopropyl;
R ₁₁ and R _{12 are} independently of one another
H or
(C ₁ -C ₆ ) alkylene- (C ₆ ) aryl;
n is 0 or 1;
m is 2 or 3;
s is 1, 2 or 3;
L represents O;
its stereoisomeric and / or tautomeric forms and / or its pharmaceutically acceptable salts. 2. The compound of formula (I) according to claim 1, in which R ₁ represents OH and which differs by formula (IIIa)

or formula (IIIb)

3. The compound according to one of claims 1 to 2, where R ₇ represents halogen or (C ₁ -C ₆ ) alkyl. 4. The compound according to one of claims 1 to 2, where R ₇ represents chlorine. 5. The compound according to one of claims 1 to 2, where R ₉ represents (C ₁ -C ₆ ) alkyl, phenyl or (C ₃ ) cycloalkyl. 6. The compound according to one of claims 1 to 2, where R ₉ represents allyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl or phenyl. 7. The compound according to one of claims 1 to 2, where R ₁₁ and R ₁₂ independently from each other are
H or
(C ₁ -C ₄ ) alkylene- (C ₆ ) aryl. 8. The compound according to one of claims 1 to 2, where
R ₁₁ represents H; and
R ₁₂ represents
H or
(C ₁ -C ₄ ) alkylene- (C ₆ ) aryl. 9. The compound according to one of claims 1 to 2, where R ₁₁ and R ₁₂ represent N. 10. The compound according to one of claims 1 to 2, where the bicycles formed with R ₆ are selected from the group

or

which is unsubstituted or optionally substituted with R ₉ . 11. The compound according to one of claims 1 to 2, where the adamantane formed with R ₆ is selected from compounds

,

,

or

which are unsubstituted or substituted by residues R ₉ . 12. The compound according to one of claims 1 to 2, where R ₆ together with R ₁₁ and the N atom form a (C ₅ ) heterocycloalkyl, which is connected to the cycloalkyl residue in the form of a spirocyclic system, where the ring containing system (C ₅ ) heterocycloalkyl is unsubstituted or substituted with R ₉ . 13. The compound according to one of claims 1 to 2, where m is 2 and s is 2. 14. The compound according to one of claims 1 to 2, where m is 3 and s is 1. 15. The compound according to one of claims 1 to 2, where n is 0. 16. The compound according to claim 1, selected from the group consisting of
6- (4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-allyl-4-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-amino-4-propyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-amino-4-methyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-amino-4-phenyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-amino-4-cyclopropyladamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (4-benzylaminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (3-aminoadamantan-1-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,
6- (5-aminoadamantan-2-yloxy) -7-methyl-2H-isoquinolin-1-one,
6 - {[(7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,
6 - {[(- 7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one
3,3-dioxide 6 - {[(7-amino-3- (dioxothia) bicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one or
6- (1-azaspiro [4.5] dec-8-yloxy) -7-chloro-2H-isoquinolin-1-one, their stereoisomeric and / or tautomeric forms and / or their pharmaceutically acceptable salts. 17. The compound according to claim 1, selected from the group consisting of cis-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,
trans-6- (5-aminoadamantan-2-yloxy) -7-chloro-2H-isoquinolin-1-one,
6 - {[(7-endo, 9-anti) -7-amino-3-oxabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,
6 - {[(7-endo, 9-syn) -7-amino-3-oxabicyclo [3.3.1] non-9yl] oxy} -7-chloroisoquinolin-1 (2H) -one,
6 - {[(7-endo, 9-anti) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one,
6 - {[(7-endo, 9-syn) -7-amino-3-thiabicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H) -one and
3,3-dioxide 6 - {[(7-endo, 9-anti) -7-amino-3- (dioxothia) bicyclo [3.3.1] non-9-yl] oxy} -7-chloroisoquinolin-1 (2H )-she,
their stereoisomeric and / or tautomeric forms and / or their pharmaceutically acceptable salts. 18. The compound of formula (I) and / or its pharmaceutically acceptable salt according to one of claims 1 to 2 for use as a medicine for the treatment and / or prophylaxis of diseases associated with the inhibition of Rho kinase and / or mediated Rho kinase phosphorylation myosin light chain phosphatases. 19. The use of a compound of formula (I) and / or its pharmaceutically acceptable salt according to one of claims 1-17 for the manufacture of a medicament for the treatment and / or prevention of diseases associated with the inhibition of Rho kinase and / or Rho kinase-mediated phosphatase phosphorylation light chains of myosin. 20. The use of a compound of formula (I) and / or its pharmaceutically acceptable salt according to one of claims 1-17 for the treatment and / or prevention of hypertension, pulmonary hypertension, eye hypertension, retinopathy, glaucoma, peripheral circulation disorder, occlusive peripheral artery disease ( PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, coronary heart disease, failure of ischemic destruction organs (terminal organs), pneumofibrosis, liver fibrosis, liver failure typhoid nephropathy, renal failure, kidney fibrosis, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebrovascular spasm, cerebral ischemia, pain, neuronal degeneration , spinal cord injuries, Alzheimer's disease, preterm labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and complications diabetes, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS (AIDS), osteopathy, infectious diseases of the intestinal tract caused by bacteria, the development and progression of sepsis or cancer. 21. The use of a compound of formula (I) and / or its pharmaceutically acceptable salt according to one of claims 1-17 for the treatment and / or prevention of hypertension, pulmonary hypertension, liver fibrosis, liver failure, nephropathy, renal failure, chronic obstructive pulmonary disease ( COPD), cerebrovascular spasm, pain, spinal cord injury, erectile dysfunction, restenosis of blood vessels or the development and progression of cancer. 22. A drug containing an effective amount of a compound of formula (I) and / or its pharmacologically acceptable salt according to one of claims 1 to 17, pharmaceutically acceptable excipients and carriers for the treatment and / or prevention of diseases associated with the inhibition of Rho kinase and / or Rho kinase-mediated phosphorylation of myosin light chain phosphatase.